Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors

ABSTRACT

This application relates to compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, which modulate the activity of adenosine receptors, such as subtypes A2A and A2B receptors, and are useful in the treatment of diseases related to the activity of adenosine receptors including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.

TECHNICAL FIELD

The present invention provides fused heterocycles and derivativesthereof that modulate the activity of adenosine receptors, such assubtypes A2A and A2B, and are useful in the treatment of diseasesrelated to the activity of adenosine receptors including, for example,cancer, inflammatory diseases, cardiovascular diseases andneurodegenerative diseases.

BACKGROUND

Adenosine is an extracellular signaling molecule that can modulateimmune responses through many immune cell types. Adenosine was firstrecognized as a physiologic regulator of coronary vascular tone by Druryand Szent-Gyorgyu (Sachdeva, S. and Gupta, M. Saudi PharmaceuticalJournal, 2013, 21, 245-253), however it was not until 1970 that Sattinand Rall showed that adenosine regulates cell function via occupancy ofspecific receptors on the cell surface (Sattin, A., and Rall, T. W.,1970. Mol. Pharmacol. 6, 13-23; Hasko', G., at al., 2007, Pharmacol.Ther. 113, 264-275).

Adenosine plays a vital role in various other physiological functions.It is involved in the synthesis of nucleic acids and when linked tothree phosphate groups, it forms ATP, the integral component of thecellular energy system. Adenosine can be generated by the enzymaticbreakdown of extracellular ATP, or can also be released from injuredneurons and glial cells by passing the damaged plasma membrane(Tautenhahn, M. et al. Neuropharmacology, 2012, 62, 1756-1766).Adenosine produces various pharmacological effects, both in theperiphery and in the central nervous system (CNS), through an action onspecific receptors localized on cell membranes (Matsumoto, T. et al.Pharmacol. Res., 2012, 65, 81-90). Alternative pathways forextracellular adenosine generation have been described. These pathwaysinclude the production of adenosine from nicotinamide dinucleotide (NAD)instead of ATP by the concerted action of CD38, CD203a and CD73.CD73-independent production of adenosine can also occur by otherphosphates such as alkaline phosphatase or prostate-specificphosphatase.

There are four known subtypes of adenosine receptor in humans includingA1, A2A, A2B and A3 receptors. A1 and A2A are high affinity receptors,whereas A2B and A3 are low affinity receptors. Adenosine and itsagonists can act via one or more of these receptors and can modulate theactivity of adenylate cyclase, the enzyme responsible for increasingcyclic AMP (cAMP). The different receptors have differential stimulatoryand inhibitory effects on this enzyme. Increased intracellularconcentrations of cAMP can suppress the activity of immune andinflammatory cells (Livingston, M. et al., Inflamm. Res., 2004, 53,171-178).

The A2A adenosine receptor can signal in the periphery and the CNS, withagonists explored as anti-inflammatory drugs and antagonists exploredfor neurodegenerative diseases (Carlsson, J. et al., J. Med. Chem.,2010, 53, 3748-3755). In most cell types the A2A subtype inhibitsintracellular calcium levels whereas the A2B potentiates them. The A2Areceptor generally appears to inhibit inflammatory response from immunecells (Borrmann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006).

A2B receptors are highly expressed in the gastrointestinal tract,bladder, lung and on mast cells (Antonioli, L. et al., Nature ReviewsCancer, 2013, 13, 842-857). The A2B receptor, although structurallyclosely related to the A2A receptor and able to activate adenylatecyclase, is functionally different. It has been postulated that thissubtype may utilize signal transduction systems other than adenylatecyclase (Livingston, M. et al., Inflamm. Res., 2004, 53, 171-178). Amongall the adenosine receptors, the A2B adenosine receptor is a lowaffinity receptor that is thought to remain silent under physiologicalconditions and to be activated in consequence of increased extracellularadenosine levels (Ryzhov, S. et al. Neoplasia, 2008, 10, 987-995).Activation of A2B adenosine receptor can stimulate adenylate cyclase andphospholipase C through activation of Gs and Gq proteins, respectively.Coupling to mitogen activated protein kinases has also been described(Boiiniann, T. et al., J. Med. Chem., 2009, 52(13), 3994-4006). In theimmune system, engagement of adenosine signaling can be a criticalregulatory mechanism that protects tissues against excessive immunereactions. Adenosine can negatively modulate immune responses throughmany immune cell types, including T-cells, natural-killer cells,macrophages, dendritic cells, mast cells and myeloid-derived suppressorcells (Allard, B. et al. Current Opinion in Pharmacology, 2016, 29,7-16).

In tumors, this pathway is hijacked by tumor micro-environments andsabotages the antitumor capacity of immune system, promoting cancerprogression. In the tumor micro-environment, adenosine was mainlygenerated from extracellular ATP by CD39 and CD73. Multiple cell typescan generate adenosine by expressing CD39 and CD73. This is the case fortumor cells, T-effector cells, T-regulatory cells, tumor associatedmacrophages, myeloid derived suppressive cells (MDSCs), endothelialcells, cancer-associated fibroblast (CAFs) and mesenchymal stromal/stemcells (MSCs). Hypoxia, inflammation and other immune-suppressivesignaling in tumor micro-environment can induce expression of CD39, CD73and subsequent adenosine production. As a result, adenosine level insolid tumors is unusually high compared to normal physiologicalconditions.

A2A are mostly expressed on lymphoid-derived cells, including T-effectorcells, T regulatory cells and nature killing cells. Blocking A2Areceptor can prevent downstream immunosuppressive signals thattemporarily inactivate T cells. A2B receptors are mainly expressed onmonocyte-derived cells including dendritic cells, tumor-associatedmacrophages, myeloid derived suppressive cells (MDSCs), and mesenchymalstromal/stem cells (MSCs). Blocking A2B receptor in preclinical modelscan suppress tumor growth, block metastasis, and increase thepresentation of tumor antigens.

In terms of safety profile of ADORA2A/ADORA2B (A2A/A2B) blockage, theA2A and A2B receptor knockout (KO) mice are all viable, showing nogrowth abnormalities and are fertile (Allard, B. et al. Current Opinionin Pharmacology, 2016, 29, 7-16). A2A KO mice displayed increased levelsof pro-inflammatory cytokines only upon challenge with LPS and noevidence of inflammation at baseline (Antonioli, L. et al., NatureReviews Cancer, 2013, 13, 842-857). A2B KO mice exhibited normalplatelet, red blood, and white cell counts but increased inflammation atbaseline (TNF-alpha, IL-6) in naive A2B KO mice (Antonioli, L. et al.,Nature Reviews Cancer, 2013, 13, 842-857). Exaggerated production ofTNF-alpha and IL-6 was detected following LPS treatment. A2B KO micealso exhibited increased vascular adhesion molecules that mediateinflammation as well leukocyte adhesion/rolling; enhanced mast-cellactivation; increased sensitivity to IgE-mediated anaphylaxis andincreased vascular leakage and neutrophil influx under hypoxia(Antonioli, L. et al., Nature Reviews Cancer, 2013, 13, 842-857).

In summary, there is a need to develop new adenosine receptor selectiveligands, such as for subtypes A2A and A2B, for the treatment of diseasessuch as cancer, inflammatory diseases, cardiovascular diseases andneurodegenerative diseases. This application is directed to this needand others.

SUMMARY

The present invention relates to, inter alfa, compounds of Formula (I):

or pharmaceutically acceptable salts thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting an activityof an adenosine receptor, comprising contacting the receptor with acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ora disorder associated with abnormal expression of adenosine receptors,comprising administering to said patient a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION Compounds

The present application provides, inter alfa, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X³ is N or CR³;    -   X⁴ is N or CR⁴;

Cy¹ is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy¹ are each optionally substituted with 1, 2, 3, 4,5, or 6 independently selected R⁵ substituents;

Cy² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy² are each optionally substituted with 1, 2, 3, 4,5, or 6 independently selected R⁶ substituents;

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)₂NR^(e1)R_(d1), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹ are each optionally substituted with 1, 2, 3, or 4independently selected R^(1A) substituents;

each R^(a1), R^(b1) R^(c1) and R^(d1) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(a1), R^(b1), R^(c1),and R^(d1) are each optionally substituted with 1, 2, 3, or 4independently selected R^(1A) substituents;

each R^(e1) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

each R^(1A) is independently selected from OH, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(e2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionally substituted with1, 2, 3, 4, 5, or 6 independently selected R^(2A) substituents;

each R_(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a2), R^(b2), R^(c2),and R^(d2), are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(2A) substituents;

or, any RC² and R^(d2), attached to the same N atom, together with the Natom to which they are attached, form a 4-10 membered heterocycloalkylgroup, wherein the 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, 4, 5, or 6 independently selected R^(2A)substituents;

each R^(e2) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21),C(O)NR^(c21)R^(d21), C(O)NR^(e21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(e21)NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))R^(b21),NR^(c21)S(O)NR^(c21)R^(d21), NR^(e21)S(O)R^(b21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)(═NR^(e21))R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21),S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), OS(O)₂R^(b21), SF₅, P(O)R^(f21)R^(g21),OP(O)(OR^(h21))(OR^(i21)), P(O)(OR^(h21))(OR^(i21)), andBR^(j21)R^(k21), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionally substitutedwith 1, 2, 3, 4, 5, or 6 independently selected R^(2B) substituents;

each R^(a21), R^(b21), R^(c21) and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-1 0membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21) andR^(d21) are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(2B) substituents;

or, any R^(c21) and R^(d21), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, or 6 independentlyselected R^(2B) substituents;

each R^(e21) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f21) and R^(g21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h21) and R^(i21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j21) and R^(k21) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j21) and R^(k21) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2B) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a22), SR^(a22), NHOR^(a22), C(O)R^(b22),C(O)NR^(c22)R^(d22), C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22), R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═NR^(e22))R^(b22), C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))R^(b22),NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), OS(O)₂R^(b22), SF₅, P(O)R^(f22)R^(g22),OP(O)(OR^(b22))(OR^(i22)), P(O)(OR^(h22))(OR^(i22)), andBR^(j22)R^(k22), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2C) substituents;

each R^(a22), R^(b22), R^(c22) and R^(d22) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(b22),R^(c22) and R^(d22) are each optionally substituted with 1, 2, 3, or 4independently selected R^(2C) substituents;

or, any R^(c22) and R^(d22), attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(2C) substituents;

each R^(e22) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f22) and R^(g22) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h22) and R^(i22) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R²² and R^(k22) is independently selected from OH, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy;

or any R^(j22) and R^(k22) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2C) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a23), SR^(a23), NHOR^(a23), C(O)R^(b23),C(O)NR^(c23)R^(d23), C(O)NR^(c23)(OR^(a23)), C(O)OR^(a23), OC(O)R^(b23),OC(O)NR^(c23)R^(d23), NR^(c23)R^(d23), NR^(c23)NR^(c23)R^(d23),NR^(c23)C(O)R^(b23), NR^(c23)C(O)OR^(a23), NR^(c23)C(O)NR^(c23)R^(d23),C(═NR^(e23))R^(b23), C(═NR^(e23))NR^(c23)R^(d23),NR^(c23)C(═NR^(e23))NR^(c23)R^(d23), NR^(c23)C(═NR^(e23))R^(b23),NR^(c23)S(O)NR^(c23)R^(d23), NR^(c23)S(O)R^(b23), NR^(c23)S(O)₂R^(b23),NR^(c23)S(O)(═NR^(e23))R^(b23), NR^(c23)S(O)₂NR^(c23)R^(d23),S(O)R^(b23), S(O)NR^(c23)R^(d23), S(O)₂R^(b23), S(O)₂NR^(c23)R^(d23),OS(O)(═NR^(e23))R^(b23), OS(O)₂R^(b23), SF₅, P(O)R^(f23)R^(g23),OP(O)(OR^(h23))(OR^(i23)), P(O)(OR^(h23))(OR^(i23)), andBR^(j23)R^(k23), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2D) substituents;

each R^(a23), R^(b23), R^(c23) and R^(d23) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a23), R^(b23),R^(c23) and R^(d23) are each optionally substituted with 1, 2, 3, or 4independently selected R^(2D) substituents;

or, any R^(c23) and R^(d23), attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(2D) substituents;

each R^(e23) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f23) and R^(g23) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h23) and R^(i23) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j23) and R^(k23) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j23) and R^(k23) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2D) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a24), SR^(a24),NHOR^(a24), C(O)R^(b24), C(O)NR^(c24)R^(d24), C(O)NR^(c24)(OR^(a24)),C(O)OR^(a24), OC(O)R^(b24), NHOR^(a24), C(O)R^(b24),NR^(c24)NR^(c24)R^(d24), NR^(c24)C(O)R^(b24), NR^(c24)C(O)OR^(a24),NR^(c24)C(O)NR^(c24)R^(d24), C(═NR^(e24))R^(b24),C(═NR^(e24))NR^(c24)R^(d24), NR^(c24)C(═NR^(e24))NR^(c24)R^(d24),NR^(c24)C(═NR^(e24))R^(b24), NR^(c24)S(O)NR^(c24)R^(d24),NR^(c24)S(O)R^(b24), NR^(c24)S(O)₂R^(b24),NR^(c24)S(O)(═NR^(e24))R^(b24), NR^(c24)S(O)₂NR^(c24)R^(d24),S(O)R^(b24), S(O)NR^(c24)R^(d24), S(O)₂R^(b24), S(O)₂NR^(c24)R^(d24),OS(O)(═NR^(e24))R^(b24), OS(O)₂R^(b24), SF₅, P(O)R^(f24)R^(g24),OP(O)(OR^(h24))(OR^(i24)), P(O)(OR^(h24))(OR^(i24)), andBR^(j24)R^(k24), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2D) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2E) substituents;

each R^(a24), R^(b24), R^(c24) and R^(d24) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a24), R^(b24), R^(c24) and R^(d24) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2E) substituents;

or, any R^(c24) and R^(d24), attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(2E) substituents;

each R^(e24) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f24) and R^(g24) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h24) and R^(i24) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

each R^(j24) and R^(k24) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j24) and R^(k24) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2E) is independently selected from OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylcarbonyloxy, aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

R³ is selected from H, D, halo, OH, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, amino,C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

R⁴ is selected from H, D, halo, OH, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, amino,C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

each R⁵ is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a 5), SR^(a 5), NHOR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)NR^(c5)(OR^(a 5)), C(O)OR^(a 5), OC(O)R^(bS), OC(C)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)0R^(a 5), NR^(c5)C(O)NR^(c5)R^(d5), C(=NR^(e5))R^(b5),C(=NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(c5))NR^(c5)R^(d5),NR^(e5)C(═NR^(e5))R^(b5), NR^(e5)S(O)NR^(e5)R^(d5), NR^(e5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)(═NR^(c5))R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5), OS(O)(═NR^(e5))R^(b5), OS(O)₂R^(b5), SF₅,P(O)R^(f5)R^(g5), OP(O)(OR^(h5))(OR^(i5)), P(O)(OR^(h5))(OR^(i5)), andBR^(j5)R^(k5), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are each optionally substituted with1, 2, 3, 4, 5, or 6 independently selected RSA substituents;

each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a 5), R^(b5), R^(c5)and R^(d5) are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(5A) substituents;

or, any R^(c5) and R^(d5), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, or 6 independentlyselected R^(5A) substituents;

each R^(e5) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f5) and R^(g5) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h5) and R^(i5) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j5) and R^(k5) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j5) and R^(k5) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(5A) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO13 C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

each R⁶ is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a6), SR^(a6), NHOR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)NR^(c6)(OR^(a6)), C(O)OR^(a 6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6),C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), C(═NR^(e6))R^(b6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))R^(b6), NR^(c6)S(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S9O)₂R^(b6), NR^(c6)S(O)(═NR^(e6))R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),S(O)₂NR^(c6)R^(d6), OS(O)(═NR^(e6))R^(b6), OS(O)₂R^(b6), SF₆,P(O)R^(f6)R^(g6), OP(O)(OR^(h6))(OR^(i6)), P(O)(OR^(h6))(OR^(i6)), andBR^(j6)R^(k6), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6_1,0 aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are each optionally substituted with1, 2, 3, 4, 5, or 6 independently selected R^(6A) substituents;

or, two R⁶ groups together form an oxo group;

each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b6), R^(c6)and R^(d6) are each optionally substituted with 1, 2, 3, 4, 5, or 6independently selected R^(6A) substituents;

or, any R^(c6) and R^(d6), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, 4, 5, or 6 independentlyselected R^(6A) substituents;

each R^(e6) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(f6) and R^(g6) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(h6) and R^(i6) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

each R^(j6) and R^(k6) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j6) and R^(k6) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;and

each R^(6A) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, X³ is N and X⁴ is N.

In some embodiments, X³ is CR³ and X⁴ is N.

In some embodiments, X³ is N and X⁴ is CR⁴.

In some embodiments, R³ is selected from H and C₁₋₆ alkyl.

In some embodiments, R³ is selected from H and methyl.

In some embodiments, R³ is H.

In some embodiments, R⁴ is selected from H and C₁₋₆ alkyl.

In some embodiments, R⁴ is selected from H and methyl.

In some embodiments, R⁴ is H.

In some embodiments, Cy¹ is C₆₋₁₀ aryl or 5-10 membered heteroaryl,wherein the C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R⁵ substituents.

In some embodiments, Cy¹ is phenyl optionally substituted with 1, 2, 3,or 4 independently selected R⁵ substituents; and

each R⁵ is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a 5), SR^(a 5), NHOR^(a 5), C(O)R ^(b5), C(O)NR^(c5)R^(d5),C(O)NR^(c5)(OR^(a5)), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))R^(b5), NR^(c5)S(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)(═NR^(e5))R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5), OS(O)(═NR^(e5))R^(b5), and OS(O)₂R^(b5), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁵ are each optionally substituted with 1, 2, 3, or 4independently selected R^(5A) substituents.

In some embodiments, Cy¹ is phenyl optionally substituted with 1 or 2independently selected R⁵ substituents; and

each R⁵ is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, and NO₂.

In some embodiments, Cy¹ is cyanophenyl optionally substituted withfluoro.

In some embodiments, Cy¹ is cyanophenyl.

In some embodiments, Cy¹ is 3-benzonitrile.

In some embodiment, Cy¹ is 3-(2-fluorobenzonitrile).

In some embodiments, Cy² is 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl, wherein the 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R⁶ substituents.

In some embodiments, Cy² is 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl, wherein the 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R⁶ substituents; and each R⁶ is independentlyselected from D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a6), SR^(a6), NHOR^(a 6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)NR^(c6)(OR^(a6)), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),C(═NR^(e6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))R^(b6),NR^(c6)S(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)(═NR^(e6))R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), S(O)₂NR^(c6)R^(d6),OS(O)(═NR^(e6))R^(b6), and OS(O)₂R^(b6), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(6A)substituents,

or, two R⁶ groups together form an oxo group.

In some embodiments, Cy² is 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl, wherein the 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, or 3independently selected R⁶ substituents; and

each R⁶ is independently selected from halo, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl is optionally substituted with OH,

or, two R⁶ groups together form an oxo group.

In some embodiments, Cy² is selected from pyrimidinyl, pyrazolyl,pyridinyl, dihydropyridinyl, oxazolyl, quinolinyl, and quionaxalinyl,wherein the pyrimidinyl, pyrazolyl, pyridinyl, dihydropyridinyl,oxazolyl, quinolinyl, and quionaxalinyl are each optionally substitutedwith 1, 2, or 3 independently selected R⁶ substituents; and

each R⁶ is independently selected from halo, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl is optionally substituted with OH,

or, two R⁶ groups together form an oxo group.

In some embodiments, Cy² is selected from pyrimidin-4-yl,1-ethyl-1H-pyrazol-5-yl, pyridin-4-yl, 1 -isopropyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-5-yl, 1 -methyl-6-oxo-1,6-dihydropyridin-3-yl,3-methylpyridin-4-yl, 4-(hydroxymethyl)-2-methyloxazol-5-yl,4-methyloxazol-5-yl, oxazol-5-yl, quinolin-6-yl, and quinoxalin-6-yl.

In some embodiments, R^(I) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(I) is H.

In some embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- are each optionally substituted with 1, 2,3, or 4 independently selected R^(2A) substituents.

In some embodiments, R² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents; and

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a 21), SR^(a21), NHOR^(a21), C(O)R^(b21,)C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), S(O)R^(b21), S(O)NR^(c21)R^(d21),and S(O)₂R^(b21).

In some embodiemnts, R² is phenyl-C₁₋₃ alkyl- or (5-10 memberedheteroaryl)-C₁₋₃ alkyl-, wherein the phenyl-C₁₋₃ alkyl- and (5-10membered heteroaryl)-C₁₋₃ alkyl- are each optionally substituted with 1,2, 3, or 4 independently selected R^(2A) substituents; and

each R^(2A) is independently selected from from halo, C₁₋₆ alkyl, andC₁₋₆ haloalkyl.

In some embodiemnts, R² is selected from benzyl, pyridinylmethyl,pyrazolylmethyl, and pyridinylethyl, wherein benzyl, pyridinylmethyl,pyrazolylmethyl, and pyridinylethyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents; and

each R^(2A) is independently selected from from halo, C₁₋₆ alkyl, andC₁₋₆ haloalkyl.

In some embodiments, R² is selected from pyridin-2-ylmethyl,(1-methyl-1H-pyrazol-3-yl)methyl, (3-fluoropyridin-2-yl)methyl,(6-methylpyridin-2-yl)methyl, 1-(pyridin-2-yl)ethyl,2-(pyridin-2-yl)ethyl, and 2-fluorobenzyl.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein variables R¹, R²,Cy¹ and Cy² are defined according to the definitions provided herein,such as for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or Formula (II), or apharmaceutically acceptable salt thereof, is a compound of Formula(IIa):

or a pharmaceutically acceptable salt thereof, wherein variables R², Cy¹and Cy² are defined according to the definitions provided herein, suchas for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or Formula (II), or apharmaceutically acceptable salt thereof, is a compound of Formula(IIb):

or a pharmaceutically acceptable salt thereof, wherein variables R² andCy² are defined according to the definitions provided herein, such asfor compounds of Formula (I).

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein variables R¹, R²,R³, Cy¹ and Cy² are defined according to the definitions providedherein, such as for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or Formula (III), or apharmaceutically acceptable salt thereof, is a compound of Formula(IIIa):

or a pharmaceutically acceptable salt thereof, wherein variables R², R³,Cy¹ and Cy² are defined according to the definitions provided herein,such as for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or Formula (III), or apharmaceutically acceptable salt thereof, is a compound of Formula(IIIb):

or a pharmaceutically acceptable salt thereof, wherein variables R², R³and Cy² are defined according to the definitions provided herein, suchas for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein variables R¹, R²,R4_(, Cy) ¹ and Cy² are defined according to the definitions providedherein, such as for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or Formula (IV), or apharmaceutically acceptable salt thereof, is a compound of Formula(IVa):

or a pharmaceutically acceptable salt thereof, wherein variables R², R⁴,Cy¹ and Cy² are defined according to the definitions provided herein,such as for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or Formula (IV), or apharmaceutically acceptable salt thereof, is a compound of Formula(IVb):

or a pharmaceutically acceptable salt thereof, wherein variables R², R⁴,and Cy² are defined according to the definitions provided herein, suchas for compounds of Formula (I).

In some embodiments, the compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof,

wherein n is 0, 1, or 2; and

variables X³, X⁴, R′, R², R⁵, and Cy² are defined according to thedefinitions provided herein, such as for compounds of Formula (I).

In some embodiments of the compound of Formula (I), or apharmaceutically acceptable salt thereof,

X³ is N or CR³;

X⁴ is N or CR⁴;

Cy¹ is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy¹ are each optionally substituted with 1, 2, 3, or4 independently selected R⁵ substituents;

Cy² is selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy² are each optionally substituted with 1, 2, 3, or4 independently selected R⁶ substituents;

R¹ is selected from H and C₁₋₆ alkyl;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21),C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), S(O)R^(b21), S(O)NR^(c21)R^(d21),and S(O)₂R^(b21);

each R^(a21), R^(b21), R^(c21) and R^(d21) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

or, any R^(c21) and R^(d21), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group;

R³ is selected from H, D, halo, OH, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, amino,C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

R⁴ is selected from H, D, halo, OH, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₅ cycloalkyl, amino,C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylcarbonyloxy,aminocarbonyloxy, C₁₋₃ alkylaminocarbonyloxy, di(C₁₋₃alkyl)aminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino;

each R⁵ is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a 5), SR^(a 5), NHOR^(a 5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(C)NR^(c5)(OR^(a5)), C(O)0R^(a5), OC(O)R^(b5), OC(C)NR^(c5)R^(d5),NR^(c5)R^(d5), S(O)R^(b5), S(C)NR^(c5)R^(d5), and S(O)₂R^(b5), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁵ are each optionally substituted with 1, 2, 3, or 4independently selected R^(SA) substituents;

each R^(a s), R^(b5), R^(c5) and R^(d5) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a5), R^(b5), R^(c5)and R^(d5) are each optionally substituted with 1, 2, 3, or 4independently selected R^(SA) substituents;

or, any R^(c5) and R^(d5), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(5A) substituents;

each R^(5A) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 6 alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, 6 alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₆alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; each R⁶ is independently selected from D,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a 6), SR^(a6), NHOR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)NR^(c6)(OR^(a6)), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), and S(O)₂R^(b6), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(6A)substituents,

or, two R⁶ groups together form an oxo group;

each R^(a6) K , R^(b6), R^(c6) and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a6), R^(b6), R^(c6) andR^(d6) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(6A) substituents;

or, any R^(c6) and R^(d6), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(6A) substituents; and

each R^(6A) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments of the compound of Formula (I), or apharmaceutically acceptable salt thereof,

X³ is N or CR³;

X⁴ is N or CR⁴;

wherein at least one of X³ and X⁴ is N;

Cy¹ is C₆₋₁₀ aryl optionally substituted with 1, 2, 3, or 4independently selected R⁵ substituents;

Cy² is selected from 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, wherein the 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl of Cy² are each optionally substituted with 1, 2, 3, or4 independently selected R⁶ substituents;

R¹ is selected from H and C₁₋₆ alkyl;

R² is selected from C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(2A) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, and OR^(a 21), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents;

R^(a21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl;

each R^(2B) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, and OR^(a22), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2C) substituents;

R^(a22) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl;

each R^(2C) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,and OR^(a23).

R^(a23) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl.

R³ is selected from H and C₁₋₆ alkyl;

R⁴ is selected from H and C₁₋₆ alkyl;

each R⁵ is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a5), and NR^(c5)R^(d5);

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c5) and R^(d5), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group;

each R⁶ is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a6), and NW⁶R^(d6), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁶ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(6A)substituents,

or, two R⁶ groups together form an oxo group;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c6) and R^(d6), attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group; and

each R^(6A) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C ₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, and C₁₋₆ alkylamino.

In some embodiments of the compound of Formula (I), or apharmaceutically acceptable salt thereof,

X³ is N or CH;

X⁴ is N or CH;

wherein at least one of X³ and X⁴ is N;

Cy¹ is phenyl substituted with 1 or 2 independently selected R⁵substituents;

Cy^(t) is selected from pyrimidin-4-yl, 1-ethyl-1H-pyrazol-5-yl,pyridin-4-yl, 1-isopropyl-1H-pyrazol-5-yl, 1 -methyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 3-methylpyridin-4-yl,4-(hydroxymethyl)-2-methyloxazol-5-yl, 4-methyloxazol-5-yl, oxazol-5-yl,quinolin-6-yl, and quinoxalin-6-yl;

R¹ is H;

R² is selected from pyridin-2-ylmethyl,(1-methyl-1H-pyrazol-3-yl)methyl, (3-fluoropyridin-2-yl)methyl,(6-methylpyridin-2-yl)methyl, 1-(pyridin-2-yl)ethyl,2-(pyridin-2-yl)ethyl, and 2-fluorobenzyl; and

each R⁵ is independently selected from F and CN.

In some embodiments, the compound is the (S)-enantiomer of one of thepreceding compounds, or a pharmaceutically acceptable salt thereof. Insome embodiments, the compound is the (R)-enantiomer of one of thepreceding compounds, or a pharmaceutically acceptable salt thereof.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of any “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “-C₁₋₆alkyl-”, “alkylene”, “alkenylene”, and “alkynylene” linking groups, areeach optionally replaced by a deuterium atom.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurence‘variable’ is selected from.”

Throughout the definitions, the term “C.” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m)alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,teat-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m)alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m)alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tent-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m)aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 5 to 10 carbon atoms. In some embodiments, the arylgroup is phenyl or naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In someembodiments, a halo is F. In some embodiments, a halo is Cl.

As used herein, “C. haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C.haloalkyl”, employed alone or in combinationwith other terms, refers to an alkyl group having from one halogen atomto 2s+1 halogen atoms which may be the same or different, where “s” isthe number of carbon atoms in the alkyl group, wherein the alkyl grouphas n to m carbon atoms. In some embodiments, the haloalkyl group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃, C₂F₅,CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “thio” refers to a group of formula-SH.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(n-m)alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m)alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m)alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m)alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C.alkylsulfonylamino” refers to a group offormula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C.alkylaminosulfonyl” refers to a group offormula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m)alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m)alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)alkyl)aminosulfonylamino” refers toa group of formula -NHS(O)₂N(alkyl)2, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m)alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m)alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C.alkylthio” refers to a group of formula—S-alkyl, wherein the alkyl group has n to m carbon atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m)alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m)alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “cyano-C_(1-n)alkyl” refers to a group offormula -(C_(1-n)alkylene)-CN, wherein the alkyl group has 1 to n carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms, e.g., -(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C_(1-n)alkyl” refers to a group of formula—(C_(1-n)alkylene)-OH, wherein the alkyl group has 1 to n carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms, e.g., -(C₁₋₃ alkylene)-OH.

As used herein, the term “C_(1-n)alkoxy-C_(1-n)alkyl” refers to a groupof formula —(C_(1-n)alkylene)-O (C_(1-n)alkyl), wherein the alkyl grouphas 1 to n carbon atoms. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms, e.g., —(C₁₋₆ alkylene)-O(C₁₋₆alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m)alkylcarbonyloxy” is a group of formula—OC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, “aminocarbonyloxy” is a group of formula —OC(O)—NH₂.

As used herein, “C_(n-m)alkylaminocarbonyloxy” is a group of formula—OC(O)—NH-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, “di(C.alkyl)aminocarbonyloxy” is a group of formula—OC(O)—N(alkyl)₂, wherein each alkyl group has, independently, n to mcarbon atoms.

As used herein “C_(n-m)alkoxycarbonylamino” refers to a group of formula—NHC(O)O(C_(n-m)alkyl), wherein the alkyl group has n to m carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,or 10 ring-forming carbons (i.e., C₃₋₁₀). In some embodiments, thecycloalkyl is a C₃₋₁₀ monocyclic or bicyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₄₋₇ monocyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₄₋₁₀ spirocycle or bridged cycloalkyl(e.g., a bridged bicycloalkyl group). Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S, and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, 0, S, and B. In some embodiments, the heteroaryl is a5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, and S. In someembodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2heteroatom ring members independently selected from N, O, S, and B. Insome embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1or 2 heteroatom ring members independently selected from N, O, and S. Insome embodiments, the heteroaryl group contains 3 to 10, 4 to 10, 5 to10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments,the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1ring-forming heteroatom. When the heteroaryl group contains more thanone heteroatom ring member, the heteroatoms may be the same ordifferent. Example heteroaryl groups include, but are not limited to,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,furyl, thienyl, triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4triazolyl), tetrazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), quinolinyl, isoquinolinyl,indolyl, benzothienyl, benzofuran, benzisoxazole, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl,imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl,1H-pyrazolo[4,3-b]pyridinyl, and oxadiazolyl (e.g., 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl).

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S, and B, and wherein the ring-forming carbon atomsand heteroatoms of a heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). Heterocycloalkyl groups include monocyclic and polycyclic(e.g., having 2 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or5 to 6 membered heterocycloalkyl groups. Heterocycloalkyl groups canalso include spirocycles and bridged rings (e.g., a 5 to 10 memberedbridged biheterocycloalkyl ring having one or more of the ring-formingcarbon atoms replaced by a heteroatom independently selected from N, O,S, and B). The heterocycloalkyl group can be attached through aring-forming carbon atom or a ring-forming heteroatom. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 doublebonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e. , having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments,the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1to 2 heteroatoms or 1 heteroatom. In some embodiments, theheterocycloalkyl is a monocyclic 4 to 6 membered heterocycloalkyl having1 or 2 heteroatoms independently selected from N, O, S, and B and havingone or more oxidized ring members.

In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatomsindependently selected from N, O, S, and B and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1, 2, 3,or 4 heteroatoms independently selected from N, O, and S and having oneor more oxidized ring members. In some embodiments, the heterocycloalkylis a monocyclic 5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4heteroatoms independently selected from N, O, and S and having one ormore oxidized ring members.

Non-limiting examples of heterocycloalkyl groups includepyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran,oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline,benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclop.2.1loctanyl, oxabicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl and the like. Other examples ofhetereocycloalkyls include 1,6-dihydropyridinyl (e.g.,6-oxo-1,6-dihydropyridinyl).

As used herein, “C_(o-p) cycloalkyl-C_(n-m)alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m)alkyl-” refers to a group of formulaaryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-Cn_malkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-Cn_malkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, an “alkyl linking group” is a bivalent straight chain orbranched alkyl linking group (“alkylene group”). For example, “C_(o-p)cycloalkyl-C_(n-m)alkyl-”, “C_(o-p)aryl-C_(n-m)alkyl-”,“phenyl-C_(n-m)alkyl-”, “heteroaryl-C_(n-m)alkyl-”, and“heterocycloalkyl-C_(n-m) alkyl-” contain alkyl linking groups. Examplesof “alkyl linking groups” or “alkylene groups” include methylene,ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl, propan-1,2-diyl,propan-1,1-diyl and the like.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl, or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent, e.g., R^(2A), are independentlyselected at each occurrence from the applicable list.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula (I), (II), etc.) provided herein include stereoisomers of thecompounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofa-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide-imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present disclosure can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

As will be appreciated by thosed skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as thoseprovided in the schemes below.

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” or “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3r^(d) Ed., Wiley &Sons, Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in the schemes below:

Compounds of formula 1-11 can be prepared via the synthetic routeoutlined in Scheme 1. An appropriate reaction, such as a Mitsunobureaction, between starting materials 1-1 and 1-2 can be carried outunder suitable conditions (such as using DEAD and Ph₃P) to generateintermediate 1-3. A nucleophilic aromatic substitution (SNAr) reactionof intermediate 1-3 with amine 1-4 (PG is a suitable protecting group,such as 2,4-dimethoxybenzyl) affords compound 1-5. Compound 1-5 can thenbe cross-coupled with an adduct of formula 1-6, in which M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., M isB(OR)₂, Sn(Alkyl)₃, or Zn-Hal), under standard Suzuki cross-couplingconditions (e.g., in the presence of a palladium catalyst and a suitablebase), or standard Stille cross-coupling conditions (e.g., in thepresence of a palladium catalyst), or standard Negishi cross-couplingconditions (e.g., in the presence of a palladium catalyst) to afford thecross-coupling product, which undergoes protecting group removal togenerate intermediate 1-8. Halogenation of 1-8 with an appropriatereagent, such as N-bromosuccinimide (NBS), generates intermediate 1-9.The final product 1-11 can then be prepared by reacting compound 1-9with an adduct of formula 1-10 using reaction conditions similar to thatdescribed for the preparation of 1-7 from 1-5. The sequence of the abovementioned synthetic steps can be rearranged, as deemed appropriate, tofit each analogue synthesis.

Compounds of formula 2-7 can be prepared via the synthetic routeoutlined in Scheme 2. A nucleophilic aromatic substitution (S_(N)Ar)reaction of starting material 2-1 with amine 1-4 (wherein PG is asuitable protecting group, such as 2,4-dimethoxybenzyl) affords compound2-2. An appropriate reaction, such as a Mitsunobu reaction, between 2-2and alcohol 1-2 can then be carried out under suitable conditions (suchas using DEAD and Ph3P) to generate intermediate 2-3. Compound 2-3 canbe cross-coupled with an adduct of formula 1-6, in which M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., M isB(OR)₂, Sn(Alkyl)₃, or Zn-Hal), under standard Suzuki cross-couplingconditions (e.g., in the presence of a palladium catalyst and a suitablebase), or standard Stille cross-coupling conditions (e.g., in thepresence of a palladium catalyst), or standard Negishi cross-couplingconditions (e.g., in the presence of a palladium catalyst) to afford thecross-coupling product, which undergoes protecting group removal togenerate intermediate 2-5. Halogenation of 2-5 with an appropriatereagent, such as N-bromosuccinimide (NBS), generates intermediate 2-6.The final product 2-7 can then be prepared by reacting compound 2-6 withan adduct of formula 1-10 using reaction conditions similar to thatdescribed for the preparation of 2-4 from 2-3. The sequence of the abovementioned synthetic steps can be rearranged, as deemed appropriate, tofit each analogue synthesis.

Compounds of formula 3-8 can be prepared via the synthetic routeoutlined in Scheme 3. A cyclization reaction of starting material 3-1using appropriate reagents, such as NaNO₂ and HCl, affords bicycliccompound 3-2. A coupling reaction, such as a Mitsunobu reaction, between3-2 and alcohol 1-2 can then be carried out under suitable conditions(such as using DEAD and Ph₃P) to generate intermediate 3-3. Anucleophilic aromatic substitution (SNAr) reaction of 3-3 with amine 1-4(PG is a suitable protecting group, such as 2,4-dimethoxybenzyl) affordscompound 3-4. Intermediate 3-4 can then be cross-coupled with an adductof formula 1-6, in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki cross-coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst) to afford the cross-coupling product3-5, which undergoes protecting group removal to generate 3-6.Halogenation of 3-6 with an appropriate reagent, such asN-bromosuccinimide (NBS), generates compound 3-7. The final products 3-8can then be prepared by reacting compound 3-7 with an adduct of formula1-10 using reaction conditions similar to that described for thepreparation of 3-5 from 3-4. The sequence of the above mentionedsynthetic steps can be rearranged, as deemed appropriate, to fit eachanalogue synthesis.

Methods of Use

The compounds of the present disclosure can modulate the activity ofadenosine receptors, such as subtypes A2A and A2B receptors.Accordingly, the compounds, salts or stereoisomers described herein canbe used in methods of inhibiting adenosine receptors (e.g., A2A and/orA2B receptors) by contacting the receptor with any one or more of thecompounds, salts, or compositions described herein. In some embodiments,the compounds or salts can be used in methods of inhibiting activity ofan adenosine receptor in an individual/patient in need of the inhibitionby administering an effective amount of a compound or salt of describedherein. In some embodiments, modulating is inhibiting. In someembodiments, the contacting is in vivo. In some embodiments, thecontacting is ex vivo or in vitro.

The compounds or salts described herein can be selective. By“selective,” it is meant that the compound binds to or inhibits anadenosine receptor with greater affinity or potency, respectively,compared to at least one other receptor, kinase, etc. The compounds ofthe present disclosure can also be dual antagonists (i.e., inhibitors)of adenosine receptors, e.g., A2A and A2B adenosine receptors.

Another aspect of the present disclosure pertains to methods of treatingan adenosine receptor associated disease or disorder in an individual(e.g., patient) by administering to the individual in need of suchtreatment a therapeutically effective amount or dose of one or morecompounds of the present disclosure or a pharmaceutical compositionthereof An adenosine receptor associated disease or disorder can includeany disease, disorder or condition that is directly or indirectly linkedto expression or activity of the adenosine receptor, includingoverexpression and/or abnormal activity levels.

The compounds of the present disclosure are useful in the treatment ofdiseases related to the activity of adenosine receptors including, forexample, cancer, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, immunomodulatory disorders, central nervesystem diseases, and diabetes.

Based on the compelling roles of adenosine, e.g., A2A, A2B, receptors inmultiple immunosuppressive mechanisms, developing inhibitors can boostthe immune system to suppress tumor progression. Adenosine receptorinhibitors can be used to treat, alone or in combination with othertherapies, bladder cancer, lung cancer (e.g., non-small cell lung cancer(NSCLC), lung metastasis), melanoma (e.g., metastatic melanoma), breastcancer, cervical cancer, ovarian cancer, colorectal cancer, pancreaticcancer, esophageal cancer, prostate cancer, kidney cancer, skin cancer,thyroid cancer, liver cancer, uterine cancer, head and neck cancer, andrenal cell carcinoma (Antonioli, L. et al., Nature Reviews Cancer, 2013,13, 842-857). See also, https ://globenewswire.com/news-release/2017/04/04/954192/0/en/Corvus-Pharmaceuticals-Announces-Interim-Results-from-Ongoing-Phase-1-1b-Study-Demonstrating-Safety-and-Clinical-Activity-of-Lead-Checkpoint-Inhibitor-CPI-444-in-Patients-with-Adva.html;Cekic C. et al., J Immunol, 2012, 188:198-205; Iannone, R. et al., Am. JCancer Res. 2014, 4:172-181 (study shows that both A2A and CD73 blockadeenhance the antitumor activity of anti-CTLA-4 mAb therapy in a B16F10murine melanoma model); Iannone, R. et al., Neoplasia, 2013,15:1400-1410 and Beavis Pa., et al., Proc Natl Acad Sci. USA, 2013,110:14711-14716 (study shows that A2A and CD73 blockade decreasedmetastasis in 4T1 breast tumor model with has high CD73 expression). Insome embodiments, the prostate cancer is metastatic castrate-resistantprostate carcinoma (mCRPC). In some embodiments, the colorectal canceris colorectal carcinoma (CRC).

In some embodiments, the disease or disorder is lung cancer (e.g.,non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer,head and neck squamous cell carcinoma, prostate cancer, liver cancer,color cancer, endometrial cancer, bladder cancer, skin cancer, cancer ofthe uterus, renal cancer, gastric cancer, or sarcoma. In someembodiments, the sarcoma is Askin's tumor, sarcoma botryoides,chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma,malignant schwannoma, osteosarcoma, alveolar soft part sarcoma,angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans,desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma,extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma,gastrointestinal stromal tumor (GIST), hemangiopericytoma,hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheathtumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, orundifferentiated pleomorphic sarcoma.

In some embodiments, the disease or disorder is mesothelioma oradrenocarcinoma. In some embodiments, the disease or disorder ismesothelioma. In some embodiments, the disease or disorder isadrenocarcinoma.

MDSC (myeloid-derived suppressor cells) are a heterogenous group ofimmune cells from the myeloid lineage (a family of cells that originatefrom bone marrow stem cells). MDSCs strongly expand in pathologicalsituations such as chronic infections and cancer, as a result of analtered haematopoiesis. MDSCs are discriminated from other myeloid celltypes in which they possess strong immunosuppressive activities ratherthan immunostimulatory properties. Similar to other myeloid cells, MDSCsinteract with other immune cell types including T cells, dendriticcells, macrophages and natural killer cells to regulate their functions.In some embodiments, the compounds, etc. described herein can be used inmethods realted to cancer tissue (e.g., tumors) with high infiltrationof MDSCs, including Solid tumors with high basal level of macrophageand/or MDSC infiltration.

In some embodiments, the compounds of the disclosure can be used intreating pulmonary inflammation, including bleomycin-induced pulmonaryfibrosis and injury related to adenosine deaminase deficiency (Baraldi,et al., Chem. Rev., 2008, 108, 238-263).

In some embodiments, the compounds of the disclosure can be used as atreatment for inflammatory disease such as allergic reactions (e.g., A2Badenosine receptor dependent allergic reactions) and other adenosinereceptor dependent immune reactions. Further inflammatory diseases thatcan be treated by compounds of the disclosure include respiratorydisorders, sepsis, reperfusion injury, and thrombosis.

In some embodiments, the compounds of the disclosure can be used as atreatment for cardiovascular disease such as coronary artery disease(myocardial infarction, angina pectoris, heart failure), cerebrovasculardisease (stroke, transient ischemic attack), peripheral artery disease,and aortic atherosclerosis and aneurysm. Atherosclerosis is anunderlying etiologic factor in many types of cardiovascular disease.Atherosclerosis begins in adolescence with fatty streaks, which progressto plaques in adulthood and finally results in thrombotic events thatcause occlusion of vessels leading to clinically significant morbidityand mortality. Antagonists to the A2B adenosine receptor and A2Aadenosine receptor may be beneficial in preventing atheroscleroticplaque formation (Eisenstein, A. et al., J. Cell Physiol., 2015,230(12), 2891-2897).

In some embodiments, the compounds of the disclosure can be used as atreatment for disorders in motor activity; deficiency caused bydegeneration of the striatonigral dopamine system; and Parkinson'sdisease; some of the motivational symptoms of depression (Collins, L. E.et al. Pharmacol. Biochem. Behay., 2012, 100, 498-505.).

In some embodiments, the compounds of the disclosure can be used as atreatment for diabetes and related disorders, such as insulinresistance. Diabetes affects the production of adenosine and theexpression of A2B adenosine receptors (A2BRs) that stimulate IL-6 andCRP production, insulin resistance, and the association between A2BRgene single-nucleotide polymorphisms (ADORA2B SNPs) and inflammatorymarkers. The increased A2BR signaling in diabetes may increase insulinresistance in part by elevating pro-inflammatory mediators. SelectiveA2BR blockers may be useful to treat insulin resistance (Figler, R. A.et al. Diabetes, 2011, 60 (2), 669-679).

It is believed that compounds provided herein, e.g., compounds ofFormula (I), or any of the embodiments thereof, may possess satisfactorypharmacological profile and promising biopharmaceutical properties, suchas toxicological profile, metabolism and pharmacokinetic properties,solubility, and permeability. It will be understood that determinationof appropriate biopharmaceutical properties is within the knowledge of aperson skilled in the art, e.g., determination of cytotoxicity in cellsor inhibition of certain targets or channels to determine potentialtoxicity.

The terms “individual” or “patient”, used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

-   I. Immune-Checkpoint Therapies

In some embodiments, A2A and A2B dual inhibitors provided herein can beused in combination with one or more immune checkpoint inhibitors forthe treatment of cancer as described herein. In one embodiment, thecombination with one or more immune checkpoint inhibitors as describedherein can be used for the treatment of melanoma. Compounds of thepresent disclosure can be used in combination with one or more immunecheckpoint inhibitors. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CD20, CD28, CD40,CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA,CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. Insome embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, thecompounds of the disclosure provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the A2A and A2B dual inhibitors provided herein canbe used in combination with one or more agonists of immune checkpointmolecules, e.g., OX40, CD27, OX40, GITR, and CD137 (also known as4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®),pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. Insome embodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody isMGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Otheranti-cancer agent(s) include antibody therapeutics such as 4-IBB (e.g.urelumab, utomilumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-Ll monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonalantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX4OL fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX4OLfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3, tumor specific antigens (e.g., CD70) or TGFP receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

-   II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors or one or moretherapies for the treatment of diseases, such as cancer. Examples ofdiseases and indications treatable with combination therapies includethose as described herein.

The compounds of the present disclosure can be used in combination withone or more additional pharmaceutical agents such as, for example,chemotherapeutics, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Ab1, EGFR, HER2, JAK, c-MET, VEGFR,PDGFR, c-Kit, IGF-1R, RAF and FAK kinase inhibitors. The one or moreadditional pharmaceutical agents can be administered to a patientsimultaneously or sequentially.

For example, the compounds as disclosed herein can be combined with oneor more inhibitors of the following kinases for the treatment of cancerand other diseases or disorders described herein: Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, FGFR1, FGFR2, FGFR3, FGFR4, c-Met,Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/F1t2, Flt4, EphAl, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. Non-limiting examples of inhibitors that can be combinedwith the compounds of the present disclosure for treatment of cancer andother diseases and disorders described herein include an FGFR inhibitor(FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat, NLG919,or BMS-986205), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a Piminhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3,Axl, and Mer), a histone deacetylase inhibitor (HDAC) such as an HDAC8inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor,bromo and extra terminal family members inhibitors (for example,bromodomain inhibitors or BET inhibitors such as INCB54329 andINCB57643) and an adenosine receptor antagonist or combinations thereof.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C,adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine,ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml 1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumortargeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, Toll receptor agonists, STING agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, daunorubicin,decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, dromostanolone propionate, eculizumab, epirubicin,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, ruxolitinib, rucaparib, streptozocin, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat, niraparib, veliparib, talazoparib, and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Ab1inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098,and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present disclosure with anadditional agent.

In some embodiments, the compounds of the disclosure can be used incombination with an inhibitor of JAK or PI3K8.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of thedisclosure where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating A2A and/or A2B receptors intissue samples, including human, and for identifying A2A and/or A2Bantagonists by inhibition binding of a labeled compound. Substitution ofone or more of the atoms of the compounds of the present disclosure canalso be useful in generating differentiated ADME (Adsorption,Distribution, Metabolism and Excretion.) Accordingly, the presentdisclosure includes adenosine receptor (e.g., A2A and/or A2B) assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹⁴N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsin any of the disclosed Formulas, e.g., Formula (I), can beperdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuteriumatoms. In some embodiments, all of the hydrogen atoms in a compound canbe replaced or substituted by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of any “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or“-C₁₋₆alkyl-”, “alkylene”, “alkenylene” and “alkynylene” linking groups,as described herein, are each optionally replaced by a deuterium atom.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan FThomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵ S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind an adenosine receptor by monitoringits concentration variation when contacting with the adenosine receptor,through tracking of the labeling. For example, a test compound (labeled)can be evaluated for its ability to reduce binding of another compoundwhich is known to bind to a an adenosine receptor (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the adenosine receptor directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of adenosine receptor-associateddiseases or disorders (such as, e.g., cancer, an inflammatory disease, acardiovascular disease, or a neurodegenerative disease) which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of an adenosine receptor (e.g., A2A and/or A2B) accordingto at least one assay described herein.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 30×100 mm or WatersXBridge™ C₁₈ 5 μm, 30×100 mm column, eluting with mobile phase A: 0.1%TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile;the flow rate was 60 mL/minute, the separating gradient was optimizedfor each compound using the Compound Specific Method Optimizationprotocol as described in the literature (see e.g. “Preparative LCMSPurification: Improved Compound Specific Method Optimization”, K. Blom,B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

pH=10 purifications: Waters XBridge™ C₁₈ 5 μm, 30×100 mm column, elutingwith mobile phase A: 0.1% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 60 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)).

Example 13-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

Step A. 4,6-dichloro-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridine

To a mixture of 4,6-dichloro-1H-pyrazolo[4,3-c]pyridine (1000 mg, 5.32mmol), pyridin-2-ylmethanol (0.77 mL, 7.98 mmol) and triphenylphosphine(2790 mg, 10.64 mmol) in DCM (10 mL) was added diisopropylazodicarboxylate (1.57 mL, 7.98 mmol) at 0° C. The reaction mixture wasstirred at 0° C. overnight. Direct chromatography on silica gel columnafforded the desired product (571 mg, 39%). LC-MS calculated forC_(l2)H₉Cl₂N₄: 279.0 (M+H)⁺; found: 279.3 (M+H)⁺.

Step B.6-chloro-N-(2,4-dimethoxybenzyl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-4-amine

To the mixture of4,6-dichloro-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridine (500 mg,1.791 mmol), (2,4-dimethoxyphenyl)methanamine (0.30 mL, 1.97 mmol) in1,4-dioxane (10 mL) was added triethylamine (0.30 mL, 2.15 mmol). Thereaction mixture was stirred at 110° C. overnight. Direct chromatographyon silica gel column afforded the desired product (609 mg, 83%). LC-MScalculated for C₂₁H₂₁ClN₅O₂: 410.1 (M+H)⁺; found: 410.3 (M+H)⁺.

Step C.3-(4-((2,4-dimethoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

To the mixture of6-chloro-N-(2,4-dimethoxybenzyl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-4-amine(609 mg, 1.486 mmol), (3-cyanophenyl)boronic acid (327 mg, 2.229 mmol)in 1,4-dioxane (10 mL) and water (1 mL) was added cesium carbonate (968mg, 2.97 mmol). The reaction mixture was de-gassed under N₂ and thenchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(117 mg, 0.149 mmol) was added. The mixture was stirred at 120° C. undermicrowave for 90 minutes. The reaction was quenched with 20 mL of ethylacetate and 20 mL of water. The organic phase was separated and theaqueous solution was extracted with ethyl acetate twice. The combinedextracts were dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified on silica gel column to afford thedesired product. LC-MS calculated for C₂₈H₂₅N₆O₂: 477.2 (M+H)⁺; found:477.3 (M+H)⁺.

Step D.3-(4-amino-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

The solution of3-(4-((2,4-dimethoxybenzypamino)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile(500 mg, 1.049 mmol) in TFA (5.00 mL) was stirred at 100° C. for 30minutes. TFA was evaporated under reduced pressure and then 20 mL ofsaturated NaHCO₃ aqueous solution and 20 mL of ethyl acetate were added.The organic phase was separated and the aqueous solution was extractedwith ethyl acetate twice. The combined extracts were dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedon silica gel column to afford the desired product (273 mg, 80%). LC-MScalculated for C₁₉H₁₅N₆: 327.1 (M+H)⁺; found: 327.3 (M+H)⁺.

Step E.3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

The reaction mixture of3-(4-amino-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile(273 mg, 0.836 mmol) and 1-bromopyrrolidine-2,5-dione (156 mg, 0.878mmol) in THF (10 mL) was stirred at 0° C. for 30 minutes and quenchedwith saturated NaHCO₃ aqueous solution. The organic phase was separated,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Theresulting residue was purified on silica gel column to afford thedesired product (251 mg, 74.0%). LC-MS calculated for C₁₉H₁₄BrN₆: 405.0(M+H)⁺ and 407.0 (M+H)⁺; found: 405.2 (M+H)⁺and 407.3 (M+H)⁺.

Step F.3-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile(25 mg, 0.062 mmol), 4-(tributylstannyl)pyrimidine (34.2 mg, 0.093mmol), and copper(I) chloride (7.33 mg, 0.074 mmol), lithium chloride(3.14 mg, 0.074 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.13mg, 6.17 μml) in THF (1 ml) was first purged with N₂, and then heatedand stirred at 90° C. for 2 h. The reaction was diluted with methanoland purified with prep-LCMS (pH=2) to give the desired product. LC-MScalculated for C₂₃H₁₇N₈: 405.2 (M+H)⁺; found: 405.3 (M+H)⁺.

Example 23-(4-amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

To the mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile(20 mg, 0.049 mmol) and1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(21.92 mg, 0.099 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) wasadded cesium carbonate (16.08 mg, 0.049 mmol). The resulting mixture wassparged with N₂ for 2 min and thenchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(3.88 mg, 4.94 μmop was added. The reaction mixture was stirred at 120°C. for 1.5 h and then was diluted with methanol. Direct purification onprep. HPLC afforded the desired product. LC-MS calculated for C₂₄H₂₁N₈:421.2 (M+H)⁺; found: 421.3 (M+H)⁺.

Example 33-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduresdescribed in Example 1, except by using (3-fluoropyridin-2-yl)methanolinstead of using (pyridin-2-yl)methanol. LC-MS calculated for C₂₃H₁₆FN₈:423.1 (M+H)+; found: 423.3 (M+H)⁺.

Example 43-(4-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduresdescribed in Example 1, except by using(1-methyl-1H-pyrazol-3-yl)methanol instead of using(pyridin-2-yl)methanol. LC-MS calculated for C₂₂H₁₈N₉: 408.2 (M+H)⁺;found: 408.3 (M+H)⁺.

Example 53-(4-amino-2-((6-methylpyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduresdescribed in Example 1, except by using (6-methylpyridin-2-yl)methanolinstead of using (pyridin-2-yl)methanol. LC-MS calculated for C₂₄H₁₉N₈:419.2 (M+H)⁺; found: 419.3 (M+H)⁺.

Example 63-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyridin-4-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduresdescribed in Example 2, except by using pyridin-4-ylboronic acid insteadof using1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LC-MS calculated for C₂₄H₁₈N₇: 404.2 (M+H)⁺; found: 404.3 (M+H)⁺.

Example 73-(4-amino-2-(2-fluorobenzyl)-7-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduresdescribed in Example 1, except by using (2-fluorophenyl)methanol insteadof using (pyridin-2-yl)methanol. LC-MS calculated for C₂₄H₁₇FN₇: 422.2(M+H)⁺; found: 422.3 (M+H)⁺.

Example 83-(7-amino-2-(pyridin-2-ylmethyl)-4-(pyrimidin-4-yl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

Step A.5-chloro-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-c]pyridin-7-amine

The reaction mixture of 5,7-dichloro-1H-pyrazolo[3,4-c]pyridine (1000mg, 5.32 mmol), (2,4-dimethoxyphenyl)methanamine (0.879 mL, 5.85 mmol)and triethylamine (0.890 mL, 6.38 mmol) in 1,4-dioxane (10 mL) wasstirred at 110° C. for 3 days. Direct purification on silica gel columnafforded the desired product (1.35 g, 80%). LC-MS calculated forC₁₅H₁₆ClN₄O₂: 319.1 (M+H)⁺; found: 319.3 (M+H)⁺.

Step B.5-chloro-N-(2,4-dimethoxybenzyl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-7-amine

The reaction mixture of5-chloro-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-c]pyridin-7-amine (1350mg, 4.24 mmol), pyridin-2-ylmethanol (555 mg, 5.08 mmol) andtriphenylphosphine (2222 mg, 8.47 mmol) in DCM (20 mL) was addeddiisopropyl azodicarboxylate (1.0 mL, 5.08 mmol) at 0° C. The reactionwas stirred at 0° C. overnight. Direct purification on silica gel columnafforded the desired product (535 mg, 31%). LC-MS calculated forC₂₁H₂₁ClN₅O₂: 410.1 (M+H)⁺; found: 410.2 (M+H)⁺.

Step C.3-(7((2,4-dimethoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

To the mixture of5-chloro-N-(2,4-dimethoxybenzyl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-7-amine(535 mg, 1.305 mmol) and (3-cyanophenyl)boronic acid (384 mg, 2.61 mmol)in 1,4-dioxane (10 mL) and water (1 mL) was added cesium carbonate (851mg, 2.61 mmol). The mixture was purged with N₂ andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(103 mg, 0.131 mmol) was added. The reaction mixture was stirred at 120°C. under microwave irradiation for 90 minutes. The reaction was quenchedwith 20 mL of ethyl acetate and 20 mL of water. The organic phase wasseparated and the aqueous solution was extracted with ethyl acetatetwice. The combined extracts were dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified on silicagel column to afford the desired product (420 mg, 68%). LC-MS calculatedfor C₂₈H₂₅N₆O₂: 477.2 (M+H)⁺; found: 477.3 (M+H)⁺.

Step D.3-(7-amino-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

The solution of3-(7-((2,4-dimethoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(420.3 mg, 0.882 mmol) in TFA (5 mL) was stirred at 100° C. for 30minutes. TFA was evaporated under reduced pressure and then 20 mL ofsaturated NaHCO₃ aqueous solution and 20 mL of ethyl acetate were added.The organic phase was separated and the aqueous solution was extractedwith ethyl acetate twice. The combined extracts were dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedon silica gel column to afford the desired product (244 mg, 85%). LC-MScalculated for C₁₉H₁₅N₆: 327.1 (M+H)⁺; found: 327.2 (M+H)⁺.

Step E.3-(7-amino-4-bromo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

The mixture of3-(7-amino-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(357 mg, 1.094 mmol) and 1-bromopyrrolidine-2,5-dione (204 mg, 1.149mmol) in THF (10 mL) was stirred at 0° C. for lh and then quenched withsaturated NaHCO₃ aqueous solution. The organic phase was separated,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Theresulting residue was purified on silica gel column to afford thedesired product (314 mg, 71%). LC-MS calculated for C₁₉H₁₄BrN₆: 405.0(M+H)⁺and 407.0 (M+H)⁺; found: 405.1 (M+H)⁺and 407.2 (M+H)⁺.

Step E3-(7-amino-2-(pyridin-2-ylmethyl)-4-(pyrimidin-4-yl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

A mixture of 3 -(7-amino-4-bromo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5 -yl)benzonitrile (40 mg, 0.099 mmol),4-(tributylstannyl)pyrimidine (109 mg, 0.296 mmol), and copper(I)chloride (11.73 mg, 0.118 mmol), lithium chloride (5.02 mg, 0.118 mmol)and tetrakis(triphenylphosphine)palladium(O) (11.41 mg, 9.87 μmop in THF(1 ml) was first purged with N₂, and then heated and stirred at 90° C.for 2 h. The reaction was diluted with methanol and purified withprep-LCMS (pH 2) to give the desired product. LC-MS calculated forC₂₃H₁₇N₈: 405.2 (M+H)⁺; found: 405.3 (M+H)⁺.

Example 93-(7-amino-4-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

To the mixture of3-(7-amino-4-bromo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(162 mg, 0.400 mmol) and (1-ethyl-1H-pyrazol-5-yl)boronic acid (55.9 mg,0.400 mmol) 1,4-dioxane (2.0 mL) and water (0.2 mL) was added cesiumcarbonate (260 mg, 0.799 mmol). The resulting mixture was sparged withN₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.040 mmol) was added. The reaction mixture was stirred at 120° C.under microwave irradiation for 90 min. The reaction mixture was dilutedwith methanol. Direct purification on prep. HPLC afforded the desiredproduct. LC-MS calculated for C₂₄H₂₁N₈: 421.2 (M+H)⁺; found: 421.3(M+H)⁺.

Example 103-(7-amino-2-((6-methylpyridin-2-yl)methyl)-4-(pyrimidin-4-yl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

The above title compound was synthesized according to the proceduresdescribed in Example 8, except by using (6-methylpyridin-2-yl)methanolinstead of using (pyridin-2-yl)methanol. LC-MS calculated for C₂₄H₁₉N₈:419.2 (M+H)⁺; found: 419.3 (M+H)⁺.

Example 113-(7-amino-4-(1-ethyl-1H-pyrazol-5-yl)-2-((6-methylpyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

To the mixture of3-(7-amino-4-bromo-2-((6-methylpyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(60 mg, 0.143 mmol) and (1-ethyl-1H-pyrazol-5-yl)boronic acid (20.03 mg,0.143 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL) was added cesiumcarbonate (93 mg, 0.286 mmol). The resulting mixture was sparged with N₂for 1 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.014mmol) was added. The reaction mixture was stirred at 120° C. undermicrowave irradiation for 90 min. The reaction mixture was diluted withmethanol. Direct purification on prep. HPLC (pH=2) afforded the desiredproduct. LC-MS calculated for C₂₅H₂₃N₈: 435.2 (M+H)⁺; found: 435.3(M+H)⁺.

Example 123-(7-amino-4-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

Step A. 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

Under N₂ atmosphere, a flaskwas charged with [Ir(OMe)(1,5-cod)]₂ (33 mg,0.050 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.22 mL, 1.50mmol), and pentane (2.0 mL). The resulting mixture was stirred at roomtemperature for 10 to 15 min. 4,4′-Di-tert-butyl-2,2′-dipyridyl (dtbpy)(26.8 mg, 0.10 mmol) was added and the reaction mixture was stirred foran additional 20 minutes. 4-methyloxazole (83.1 mg, 1.0 mmol) in diethylether (2.0 mL) was then added and the resulting mixture was stirred atroom temperature until completion. The solvent was removed under reducedpressure, and the crude material was washed with pentane to furnish thedesired product. LC-MS calculated for C₁₀H₁₇BNO₃: 210.1 (M+H)+; found:210.1 (M+H)+.

Step B.3-(7-amino-4-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

Cesium carbonate (80 mg, 0.247 mmol) was added to the mixture of3-(7-amino-4-bromo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(50 mg, 0.123 mmol) and4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (25.8mg, 0.123 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL). Theresulting mixture was sparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(9.71mg, 0.012 mmol) was added. The reaction mixture was stirred at 120° C.under microwave irradiation for 90 min. The reaction mixture was dilutedwith methanol. Direct purification on prep. HPLC afforded the desiredproduct. LC-MS calculated for C₂₃H₁₈N₇O: 408.2 (M+H)⁺; found: 408.2(M+H)⁺.

Example 133-(7-amino-4-(4-methyloxazol-5-yl)-2-((6-methylpyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

Cesium carbonate (78 mg, 0.239 mmol) was added to the mixture of3-(7-amino-4-bromo-2-((6-methylpyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(50 mg, 0.119 mmol),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (24.93mg, 0.119 mmol) in 1,4-dioxane (2.0 ml) and water (0.2 ml) and then thereaction was sparged with N₂ for 2 min. Afterchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.012 mmol) was added, the reaction was stirred at 120° C. for 1.5 hunder microwave irradiation. The reaction mixture was diluted withmethanol. Direct purification on prep. HPLC afforded the desiredproduct. LC-MS calculated for C₂₄H₂₀N₇O: 422.2 (M+H)⁺; found: 422.2(M+H)⁺.

Example 143-(7-amino-4-(1-ethyl-1H-pyrazol-5-yl)-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

Step A.5-chloro-N-(2,4-dimethoxybenzyl)-2-((3-fluoropyridin-2-yOmethyl)-2H-pyrazolo[3,4-c]pyridin-7-amine

To the mixture of5-chloro-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-c]pyridin-7-amine (1000mg, 3.14 mmol), (3-fluoropyridin-2-yl)methanol (0.379 mL, 3.76 mmol),and triphenylphosphine (1646 mg, 6.27 mmol) in DCM (15 mL) was addeddiisopropyl azodicarboxylate (0.741 mL, 3.76 mmol) at 0° C. The reactionmixture was stirred at 0° C. overnight. Direct purification on silicagel column afforded the desired product (477 mg, 36%). LC-MS calculatedfor C₂₁H₂₀ClFn₅o₂: 428.1 (M+H)⁺; found: 428.2 (M+H)⁺.

Step B.3-(7-((2,4-dimethoxybenzyl)amino)-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

To the mixture of5-chloro-N-(2,4-dimethoxybenzyl)-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-7-amine(1150 mg, 2.69 mmol) and (3-cyanophenyl)boronic acid (790 mg, 5.38 mmol)in 1,4-dioxane (10.0 mL) and water (1.00 mL) was added cesium carbonate(1751 mg, 5.38 mmol). The resulting mixture was sparged with N₂ for 2min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(211mg, 0.269 mmol) was added. The reaction mixture was stirred at 120° C.under microwave irradiation for 90 minutes. The reaction was quenchedwith 20 mL of ethyl acetate and 20 mL of water. The organic phase wasseparated and the aqueous solution was extracted with ethyl acetatetwice. The combined extracts were dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified on silicagel column to afford the desired product, (647 mg, 49%). LC-MScalculated for C₂₈H₂₄FN₆O₂: 495.2 (M+H)⁺; found: 495.2 (M+H)⁺.

Step C.3-(7-amino-2-((3-fluoropyridin-2-Amethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

The solution of3-(7-((2,4-dimethoxybenzypamino)-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(647.3 mg, 1.309 mmol, 48.7% yield) in TFA (5 mL) was stirred at 100° C.for 30 min. TFA was evaporated under reduced pressure and then 20 mL ofsaturated NaHCO₃ aqueous solution and 20 mL of ethyl acetate were added.The organic phase was separated and the aqueous solution was extractedwith ethyl acetate twice. The combined extracts were dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedon silica gel column to afford the desired product (374 mg, 83%). LC-MScalculated for C₁₉H₁₄FN₆: 345.1 (M+H)⁺; found: 345.3 (M+H)⁺.

Step D.3-(7-amino-4-bromo-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

The mixture of3-(7-amino-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(2000 mg, 5.81 mmol) and 1-bromopyrrolidine-2,5-dione (2067 mg, 11.62mmol) in THF (10 mL) was stirred at 0° C. for 1 h. Direct purificationon silica gel column afforded the desired product. LC-MS calculated forC₁₉H₁₃BrFN₆: 423.0 (M+H)⁺and 425.0 (M+H)⁺; found: 423.0 (M+H)⁺and 425.0(M+H)⁺.

Step E.3-(7-amino-4-(1-ethyl-1H-pyrazol-5-yl)-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

Cesium carbonate (30.8 mg, 0.095 mmol) was added to the mixture of3-(7-amino-4-bromo-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile(20 mg, 0.047 mmol) and1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(10.49 mg, 0.047 mmol) in 1,4-dioxane (2.0 mL) and water (2 mL). Thereaction was sparged with N₂ for 2 min and thenchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4.73 umol) was added. The resulting reaction mixture was stirred at120° C. under microwave irradiation for 1.5 h. The reaction mixture wasdiluted with methanol. Direct purification on prep. HPLC afforded thedesired product. LC-MS calculated for C₂₄H₂₀FN₈: 439.2 (M+H)⁺; found:439.3 (M+H)⁺.

Example 153-(7-amino-2-((3-fluoropyridin-2-yl)methyl)-4-(pyrimidin-4-yl)-2H-pyrazolo[3,4-c]pyridin-5-yl)benzonitrile

The mixture of3-(7-amino-4-bromo-2-((3-fluoropyridin-2-yl)methyl)-2H-pyrazolo[3,4-c]pyridin-5-yObenzonitrile(20 mg, 0.047 mmol), 4-(tributylstannyl)pyrimidine (52.3 mg, 0.142mmol), copper(I) chloride (5.61 mg, 0.057 mmol), lithium chloride (2.404mg, 0.057 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.46 mg,4.73 μmop in THF (1 ml) was first purged with N₂, and then heated andstirred at 90° C. for 2 h. The reaction was diluted with methanol andpurified with prep-LCMS (pH=2) to give the final desired product. LC-MScalculated for C₂₃H₁₆FN₈: 423.1 (M+H)⁺; found: 423.3 (M+H)⁺.

Example 163-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Step A. 4,6-dichloro-3H-[1,2,3]triazolo[4,5-c]pyridine

A solution of NaNO₂ (3.88 g, 56.2 mmol) in water (3mL) was added to asolution of 2,6-dichloropyridine-3,4-diamine (10 g, 56 mmol) inhydrochloric Acid, 37% (5 mL) at 0° C. The solution was stirred for 30min. Water (20 mL) was added and the white precipitate was filtered,washed with water, and dried to give the desired product. LC-MScalculated for C₅H₃Cl₂N₄: 189.0 (M+H)⁺; found: 189.0 (M+H)⁺.

Step B.6-chloro-N-(2,4-dimethoxybenzyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4-amine

The mixture of 4,6-dichloro-3H-[1,2,3]triazolo[4,5-c]pyridine (600 mg,3.17 mmol), (2,4-dimethoxyphenyl)methanamine (0.53mL1, 3.49 mmol) andtriethylamine (0.53 mL, 3.81 mmol) in 1,4-dioxane (10 mL) was stirred at110° C. for 3 days. Direct purification on silica gel column affordedthe desired product (875 mg, 86%). LC-MS calculated for C₁₄H₁₅ClN₅O₂:320.1 (M+H)⁺; found: 320.3 (M+H)⁺.

Step C.6-chloro-N-(2,4-dimethoxybenzyl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine

The mixture of6-chloro-N-(2,4-dimethoxybenzyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(875 mg, 2.74 mmol), pyridin-2-ylmethanol (0.317 mL, 3.28 mmol) andtriphenylphosphine (1436 mg, 5.47 mmol) in DCM (20 mL) was addeddiisopropyl azodicarboxylate (0.647 mL, 3.28 mmol)at 0° C. The resultingmixture was stirred at 0° C. for 1 h. Direct purification on silica gelcolumn afforded the desired product (375 mg, 33.4% yield). LC-MScalculated for C₂₀H₂₀ClN₆O₂: 411.1 (M+H)⁺; found: 411.2 (M+H)⁺.

Step D.3-(4-((2,4-dimethoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

To the mixture of6-chloro-N-(2,4-dimethoxybenzyl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(375 mg, 0.913 mmol) and (3-cyanophenyl)boronic acid (268 mg, 1.825mmol) in 1,4-dioxane (10 mL) and water (1.00 mL) was added cesiumcarbonate (595 mg, 1.825 mmol). The resulting mixture was purged with N₂and then chloro(2-dicyclohexylphosphino-2′,4′,6 ′-triisopropyl-1,1‘-biphenyl) [2-(2 ’-amino-1,1 biphenyl)]palladium(II) (71.8 mg, 0.091mmol) was added. The reaction mixture was stirred at 120° C. undermicrowave irradiation for 90 min. The reaction was quenched with 20 mLof ethyl acetate and 20 mL of water. The organic phase was separated andthe aqueous solution was extracted with ethyl acetate twice. Thecombined extracts were dried over Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified on silica gel column toafford the desired product (300 mg, 68.9%). LC-MS calculated forC₂₇H₂₄N₇O₂: 478.2 (M+H)⁺; found: 478.3 (M+H)⁺.

Step E.3-(4-amino-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The solution of3-(4-((2,4-dimethoxybenzyl)amino)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(300.3 mg, 0.629 mmol) in TFA (5 mL) was stirred at 100° C. for 30 min.TFA was evaporated under reduced pressure and then 20 mL of saturatedNaHCO₃ aqueous solution and 20 mL of ethyl acetate were added. Theorganic phase was separated and the aqueous solution was extracted withethyl acetate twice. The combined extracts were dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedon silica gel column to afford the desired product (175 mg, 85%). LC-MScalculated for C₁₈H₁₄N₇: 328.1 (M+H)⁺; found: 328.2 (M+H)⁺.

Step F.3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of 3 -(4-amino-2-(pyri din-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile (175 mg, 0.535 mmol) and1-bromopyrrolidine-2,5-dione (100 mg, 0.561 mmol) in THF (10 mL) wasstirred at 0° C. for 30 min and then quenched with saturated NaHCO₃aqueous solution. The organic phase was separated, dried over Na₂SO₄,filtered and evaporated under reduced pressure. The resulting residuewas purified on silica gel column to afforded the desired product (135mg, 62.2%). LC-MS calculated for C₁₈H₁₃BrN₇: 406.0 (M+H)⁺and 408.0(M+H)⁺; found: 406.1 (M+H)⁺and 408.2 (M+H)⁺.

Step G.3-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(182 mg, 0.448 mmol), 4-(tributylstannyl)pyrimidine (496 mg, 1.344mmol), and copper(I) chloride (53.2 mg, 0.538 mmol), lithium chloride(22.79 mg, 0.538 mmol) and tetrakis(triphenylphosphine)palladium(O)(51.8 mg, 0.045 mmol) in THF (1 ml) was first purged with N₂, and thenheated and stirred at 90° C. for 2 h. The reaction was diluted withmethanol and purified with prep-LCMS (pH=2) to give the desired product.LC-MS calculated for C₂₂H₁₆N₉: 406.2 (M+H)⁺; found: 406.2 (M+H)⁺.

Example 173-(4-amino-7-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (30.8 mg, 0.095 mmol) was added to the mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(20 mg, 0.047 mmol) and4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (9.88mg, 0.047 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL). The reactionwas sparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(3.5 mg, 4.73 umol) was added. The reaction was stirred at 120° C. undermicrowave irradiation for 1.5 h. The mixture was diluted with methanol.Direct purification on prep. HPLC (pH=2) afforded the desired product.LC-MS calculated for C₂₂H₁₇N₈O: 409.2 (M+H)⁺; found: 409.2 (M+H)⁺.

Example 183-(4-amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (292 mg, 0.896 mmol) was added to the mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(182 mg, 0.448 mmol) and (1-ethyl-1H-pyrazol-5-yl)boronic acid (62.7 mg,0.448 mmol) in 1,4-dioxane (2 ml) and water (2 ml). The resultingreaction mixture was sparged with N₂ for 2 min and thenchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.045 mmol) was added. The reaction mixture was stirred at 120° C. for1.5 h. The reaction mixture was diluted with methanol. Directpurification on prep. HPLC afforded the desired product. LC-MScalculated for C₂₃H₂₀N₉: 422.2 (M+H)⁺; found: 422.3 (M+H)⁺.

Example 193-(4-amino-7-(3-methylpyridin-4-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 18, except by using (3-methylpyridin-4-yl)boronicacid instead of using (1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MScalculated for C₂₄H₁₉N₈: 419.2 (M+H)⁺; found: 419.3 (M+H)⁺.

Example 203-(4-amino-7-(4-(hydroxymethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (80 mg, 0.246 mmol)was added to a mixture of3-(4-amino-7-bromo-2-(pyri din-2-ylmethyl)-2H-[1,2,3]triazolo [4,5-c]pyridin-6-yl)benzonitrile (50 mg, 0.123 mmol) and(4-(((tert-butyldimethylsily0oxy)methyl)-2-methyloxazol-5-yOboronic acid(66.8 mg, 0.246 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 ml). Thereaction was sparged with N₂ for 1 min andchloro(2-dicyclohexylphosphino-2′,4′,6‘-triisopropyl-1,1’-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.012mmol) was added. The reaction was stirred at 120° C. for 1.5 h. TFA (1.0ml, 12.98 mmol) was added and the reaction mixture was stirred at 100°C. for 60 min. The mixture was diluted with methanol. Directpurification on prep. HPLC afforded the desired product. LC-MScalculated for C₂₃H₁₉N₈O₂: 439.2 (M+H)⁺; found: 439.3 (M+H)⁺.

Example 213-(4-amino-7-(oxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 18, except by using oxazol-5-ylboronic acid insteadof using (1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MS calculated forC₂₁H₁₅N₈O: 395.1 (M+H)⁺; found: 395.3 (M+H)⁺.

Example 223-(4-amino-2-(pyridin-2-ylmethyl)-7-(quinolin-6-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 18, except by using quinolin-6-ylboronic acidinstead of using (1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MS calculatedfor C₂₇H₁₉N₈: 455.2 (M+H)⁺; found: 455.3 (M+H)⁺.

Example 233-(4-amino-2-(pyridin-2-ylmethyl)-7-(quinoxalin-6-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 18, except by using quinoxalin-6-ylboronic acidinstead of using (1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MS calculatedfor C₂₆H₁₈N₉: 456.2 (M+H)⁺; found: 456.3 (M+H)⁺.

Example 243-(4-amino-2-((6-methylpyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Step A6-chloro-N-(2,4-dimethoxybenzyl)-N-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4-amine

The mixture of 4,6-dichloro-3H-[1,2,3]triazolo[4,5-c]pyridine (600 mg,3.17 mmol), bis(4-methoxybenzyl)amine (899 mg, 3.49 mmol) andtriethylamine (531 μl, 3.81 mmol) in 1,4-dioxane (1.7 mL) was stirred at110° C. for 3 days. Direct purification on silica gel column affordedthe desired product (875 mg, 63%). LC-MS calculated for C₂₂H₂₃ClN₅O₃:440.1 (M+H)⁺; found: 440.3 (M+H)⁺.

Step B.6-chloro-N,N-bis(4-methoxybenzyl)-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine

To the mixture of6-chloro-N,N-bis(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(875 mg, 2.135 mmol), (6-methylpyridin-2-yl)methanol (315 mg, 2.56 mmol)and triphenylphosphine (1120 mg, 4.27 mmol) in DCM (20 mL) was addeddiisopropyl azodicarboxylate (0.504 mL, 2.56 mmol) at 0° C. The reactionmixture was stirred at 0° C. overnight. Direct purification on silicagel afforded the desired product (353 mg, 32%). LC-MS calculated forC₂₈H₂₈ClN₆O₂: 515.2 (M+H)⁺; found: 515.2 (M+H)⁺.

Step C.3-(4-(bis(4-methoxybenzyl)amino)-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (447 mg, 1.371 mmol) was added to the mixture of6-chloro-N,N-bis(4-methoxybenzyl)-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5 -c]pyridin-4-amine (353 mg, 0.685 mmol) and (3-cyanophenyl)boronicacid (201 mg, 1.371 mmol) in 1,4-dioxane (10 mL) and water (1.00 mL).The resulting reaction mixture was sparged with N₂ for 2 min.Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(53.9 mg, 0.069 mmol) was added. The reaction was stirred at 120° C.under microwave irradiation for 1.5 h. The reaction was quenched with 20mL of ethyl acetate and 20 mL of water. The organic phase was separatedand the aqueous solution was extracted with ethyl acetate twice. Thecombined extracts were dried over Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified on silica gel column toafford the desired product (280 mg, 70.3%). LC-MS calculated forC₃₅H₃₂N₇O₂: 582.3 (M+H)⁺; found: 582.3 (M+H)⁺.

Step D.3-(4-amino-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The solution of3-(4-(bis(4-methoxybenzyl)amino)-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(280.3 mg, 0.482 mmol,) in TFA (5 mL) was stirred at 100° C. for 1 h.TFA was evaporated under reduced pressure and then 20 mL of saturatedNaHCO₃ aqueous solution and 20 mL of ethyl acetate were added. Theorganic phase was separated and the aqueous solution was extracted withethyl acetate twice. The combined extracts were dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedon silica gel column to afford the desired product (136 mg, 58%). LC-MScalculated for C₁₉H₁₆N₇: 342.1 (M+H)⁺; found: 342.3 (M+H)⁺.

Step E.3-(4-amino-7-bromo-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of3-(4-amino-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(136 mg, 0.398 mmol) and 1-bromopyrrolidine-2,5-dione (142 mg, 0.797mmol) in THF (10 mL) was stirred at 0° C. for 1 h. Direct purificationon silica gel afforded the desired product (133 mg, 79%). LC-MScalculated for C₁₉H₁₅BrN₇: 420.1 (M+H)⁺and 422.1 (M+H)⁺; found: 420.1(M+H)⁺and 422.2 (M+H)⁺.

Step F.3-(4-amino-24(6-methylpyridin-2-yl)methyl)-7-(pyrimidin-4-y0-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of3-(4-amino-7-bromo-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(182 mg, 0.433 mmol), 4-(tributylstannyl)pyrimidine (480 mg, 1.299mmol), and copper(I) chloride (51.4 mg, 0.520 mmol), lithium chloride(22.03 mg, 0.520 mmol) and tetrakis(triphenylphosphine)palladium(0)(50.0 mg, 0.043 mmol) in THF (1 ml) was first purged with N₂, and thenheated and stirred at 90° C. for 2 h. The reaction was diluted withmethanol and purified with prep-LCMS (pH=2) to give the desired product.LC-MS calculated for C₂₃H₁₈N9: 420.2 (M+H)⁺; found: 420.3 (M+H)⁺.

Example 253-(4-amino-2-((6-methylpyridin-2-yl)methyl)-7-(pyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (78 mg, 0.238 mmol) was added to the mixture of3-(4-amino-7-bromo-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yObenzonitrile(50 mg, 0.119 mmol) and pyridin-4-ylboronic acid (14.62 mg, 0.119 mmol)in 1,4-dioxane (2.0 mL) and water (0.2 mL). The resulting mixture wassparged with N₂ for 25 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(9.36 mg, 0.012 mmol) was added. The reaction was stirred at 120° C. for1.5 h under microwave irradiation. The reaction mixture was diluted withmethanol. Direct purification on prep. HPLC afforded the desiredproduct. LC-MS calculated for C₂₄H₁₉N₈: 419.2 (M+H)⁺; found: 419.3(M+H)⁺.

Example 263-(4-amino-2-((6-methylpyridin-2-yl)methyl)-7-(3-methylpyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 25, except by using (3-methylpyridin-4-yl)boronicacid instead of using pyridin-4-ylboronic acid. LC-MS calculated forC₂₅H₂₁N₈: 433.2 (M+H)⁺; found: 433.3 (M+H)⁺.

Example 273-(4-amino-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 25, except by using(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid instead of usingpyridin-4-ylboronic acid. LC-MS calculated for C₂₅H₂₁N₈O: 449.2 (M+H)⁺;found: 449.3 (M+H)⁺.

Example 283-(4-amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 25, except by using(1-ethyl-1H-pyrazol-5-yl)boronic acid instead of usingpyridin-4-ylboronic acid. LC-MS calculated for C₂₄H₂₂N₉: 436.2 (M+H)⁺;found: 436.3 (M+H)⁺.

Example 293-(4-amino-7-(4-methyloxazol-5-yl)-2-((6-methylpyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 25, except by using4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole insteadof using pyridin-4-ylboronic acid. LC-MS calculated for C₂₅H₂₁N₈O: 423.2(M+H)⁺; found: 423.3 (M+H)⁺.

Example 303-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Step A.6-chloro-N-(2,4-dimethoxybenzyl)-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine

To the mixture of6-chloro-N-(2,4-dimethoxybenzyl)-3H41,2,31triazolo[4,5-c]pyridin-4-amine(1000 mg, 3.13 mmol), (3-fluoropyridin-2-yl)methanol (477 mg, 3.75 mmol)and triphenylphosphine (1641 mg, 6.25 mmol) in DCM (1.7 mL) was addeddiisopropyl azodicarboxylate (739 μl, 3.75 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 1 h. Direct purification on silica gelcolumn afforded the desired product (433 mg, 32%). LC-MS calculated forC₂₀H₁₉ClFN₆O₂: 429.1 (M+H)⁺; found: 429.3 (M+H)⁺.

Step B.3-(4-((2,4-dimethoxybenzyl)amino)-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (658 mg, 2.019 mmol) was added to the mixture of6-chloro-N-(2,4-dimethoxybenzyl)-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(433 mg, 1.010 mmol) and (3-cyanophenyl)boronic acid (297 mg, 2.019mmol) in 1,4-dioxane (10.0 mL) and water (1.0 mL). The resulting mixturewas sparged with N₂ for 2 min and(SP-4-4)-[2′-Amino[1,1′-biphenyl]-2-yl]chloro[dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine]palladium(79 mg, 0.101 mmol) was added. The reaction mixture was stirred at 120°C. for 1.5 h under microwave irradiation. The reaction was quenched with20 mL of ethyl acetate and 20 mL of water. The organic phase wasseparated and the aqueous solution was extracted with ethyl acetatetwice. The combined extracts were dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified on silicagel column to afford the desired product (357 mg, 71%). LC-MS calculatedfor C₂₇H₂₃FN₇O₂: 496.2 (M+H)⁺; found: 496.3 (M+H)⁺.

Step C.3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The solution of3-(4-((2,4-dimethoxybenzyl)amino)-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(357.3 mg, 0.721 mmol) in TFA (5 mL) was stirred at 100° C. for 1 h. TFAwas evaporated under reduced pressure and then 20 mL of saturated NaHCO₃aqueous solution and 20 mL of ethyl acetate were added. The organicphase was separated and the aqueous solution was extracted with ethylacetate twice. The combined extracts were dried over Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified onsilica gel column to afford the desired product (213 mg, 61%). LC-MS m/zcalculated for C₁₈H₁₃FN₇: 346.1 (M+H)⁺; found: 346.3 (M+H)⁺.

Step D.3-(4-amino-7-bromo-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-2H41,2,31triazolo[4,5-c]pyridin-6-yl0benzonitrile(213 mg, 0.617 mmol) and 1-bromopyrrolidine-2,5-dione (220 mg, 1.234mmol) in THF (5 mL) was stirred at 0° C. for 1 h. Direct purification onsilica gel afforded the desired product(175 mg, 67%). LC-MS calculatedfor C₁₈H₁₂BrFN₇: 424.0 (M+H)⁺and 426.0 (M+H)⁺; found: 424.3 (M+H)⁺and426.3 (M+H)⁺.

Step E.3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of3-(4-amino-7-bromo-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(220 mg, 0.519 mmol), 4-(tributylstannyl)pyrimidine (383 mg, 1.037mmol), and copper(I) chloride (61.6 mg, 0.622 mmol), lithium chloride(26.4 mg, 0.622 mmol) and tetrakis(triphenylphosphine)palladium(0) (59.9mg, 0.052 mmol) in THF (1 mL) was first purged with N₂, and then heatedand stirred at 90° C. for 2 h. The reaction was diluted with methanoland purified with prep-LCMS (pH=2) to give the desired product. ¹H NMR(500 MHz, DMSO-d₆) ppm 8.98 (s, 1H), 8.77 (d, J=5.02 Hz, 1H), 8.38 (dd,J₁=4.60 Hz, J₂ =1.32 Hz, 1H), 7.90-8.30 (bs, 2H), 7.76-7.89 (m, 3H),7.66 (dd, J₁=5.25 Hz, J₂ =1.25 Hz, 1H), 7.45-7.58 (m, 3H), 6.25 (s, 2H).LC-MS calculated for C₂₂H₁₅FN₉: 424.1 (M+H)⁺; found: 424.3 (M+H)⁺.

Example 313-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (46.1 mg, 0.141 mmol) was added to the mixture of3-(4-amino-7-bromo-2-((3-fluoropyridin-2-yOmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(30 mg, 0.071 mmol) and pyridin-4-ylboronic acid (17.38 mg, 0.141 mmol)in 1,4-dioxane (2 mL) and water (0.2 mL). The resulting mixture wassparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(5.56 mg, 7.07 umol) was added. The reaction mixture was stirred at 120°C. for 1.5 h under microwave irradiation. The reaction mixture wasdiluted with methanol. Direct purification on pre. HPLC afforded thedesired product. LC-MS calculated for C₂₃H₁₆FN₈: 423.1 (M+H)⁺; found:423.3 (M+H)⁺.

Example 323-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 31, except by using(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid instead of usingpyridin-4-ylboronic acid. LC-MS calculated for C₂₄H₁₈FN₈O: 453.2 (M+H)⁺;found: 453.3 (M+H)⁺.

Example 333-(4-amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-((3-fluoropyridin-2-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in

Example 31, except by using (1-ethyl-1H-pyrazol-5-yl)boronic acidinstead of using pyridin-4-ylboronic acid. LC-MS calculated forC₂₃H₁₉FN₉: 440.2 (M+H)⁺; found: 440.3 (M+H)⁺.

Example 343-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(1-isopropyl-1H-pyrazol-5-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 31, except by using(1-isopropyl-1H-pyrazol-5-yl)boronic acid instead of usingpyridin-4-ylboronic acid. LC-MS calculated for C₂₄H₂₁FN₉: 454.2 (M+H)⁺;found: 454.3 (M+H)⁺.

Example 353-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(1-methyl-1H-pyrazol-5-yl)-2H-[1,2,3]triazolo [4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 31, except by using(1-methyl-1H-pyrazol-5-yl)boronic acid instead of usingpyridin-4-ylboronic acid. LC-MS calculated for C₂₂H₁₇FN₉: 426.2 (M+H)⁺;found: 426.3 (M+H)⁺.

Example 36.3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(4-methyloxazol-5-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 31, except by using4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole insteadof using pyridin-4-ylboronic acid. LC-MS calculated for C₂₂H₁₆FN₈O:427.1 (M+H)⁺; found: 427.3 (M+H)⁺.

Example 373-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(quinoxalin-6-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 31, except by using quinoxalin-6-ylboronic acidinstead of using pyridin-4-ylboronic acid. LC-MS calculated forC₂₆H₁₇FN₉: 474.2 (M+H)⁺; found: 474.3 (M+H)⁺.

Example 383-(4-amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

Step A. 3-(4-amino-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

To the mixtureof6-chloro-N-(2,4-dimethoxybenzyl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(300 mg, 0.730 mmol) and (3-cyano-2-fluorophenyl)boronic acid (241 mg,1.460 mmol) was added cesium carbonate (476 mg, 1.460 mmol). Thereaction was sparged with N₂ for 2 min. The reaction was stirred at 120°C. for 1.5 h. The reaction was quenched with 20 mL of ethyl acetate and20 mL of water. The organic phase was separated and the aqueous solutionwas extracted with ethyl acetate twice. The combined extracts were driedover Na₂SO₄, filtered and evaporated under reduced pressure. The residuewas purified on silica gel column to afford the desired product (260 mg,72%).

The intermediate obtained from the previous step (260 mg, 0.525 mmol) inTFA (5.0 mL), and the reaction was stirred at 100° C. for 1 h. TFA wasevaporated under reduced pressure and then 20 mL of saturated NaHCO₃aqueous solution and 20 mL of ethyl acetate were added. The organicphase was separated and the aqueous solution was extracted with ethylacetate twice. The combined extracts were dried over Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified onsilica gel column to afford the desired product (151 mg, 83%). LC-MScalculated for C₁₈H₁₃FN₇: 346.1 (M+H)⁺; found: 346.3 (M+H)⁺.

Step B.3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

The mixture of3-(4-amino-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile(151 mg, 0.437 mmol) and 1-bromopyrrolidine-2,5-dione (86 mg, 0.481mmol) in THF (10 mL) was stirred at 0° C. for 1 h. Direct purificationon silica gel afforded the desired product (144 mg, 78%). LC-MScalculated for C₁₈H₁₂BrFN₇: 424.0 (M+H)⁺and 426.0 (M+H)⁺; found: 424.3(M+H)⁺and 426.3 (M+H)⁺.

Step C.3-(4-amino-7-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

Cesium carbonate (23.04 mg, 0.071 mmol) was added to the mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile(30 mg, 0.071 mmol) and (1-ethyl-1H-pyrazol-5-yl)boronic acid (19.79 mg,0.141 mmol) in 1,4-dioxane (2.0 ml) and water (0.2 ml). The reaction wassparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(7.07μmol) was added. The reaction was stirred at 120° C. for 1.5 h. Directpurification on prep. HPLC afforded the desired product. LC-MScalculated for C₂₃H₁₉FN₉: 440.2 (M+H)⁺; found: 440.3 (M+H)⁺.

Example 393-(4-amino-7-(1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 38, except by using(1-methyl-1H-pyrazol-5-yl)boronic acid instead of using(1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MS calculated for C₂₂H₁₇FN₉:426.2 (M+H)⁺; found: 426.3 (M+H)⁺.

Example 403-(4-amino-7-(1-isopropyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 38, except by using(1-isopropyl-1H-pyrazol-5-yl)boronic acid instead of using(1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MS calculated for C₂₄H₂₁FN₉:454.2 (M+H)⁺; found: 454.3 (M+H)⁺.

Example 413-(4-amino-7-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 38, except by using (4-methyloxazol-5-yl)boronicacid instead of using (1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MScalculated for C₂₂H₁₆F₈O: 427.1 (M+H)+; found: 427.3 (M+H)⁺.

Example 423-(4-amino-7-(4-(hydroxymethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

Step A. 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyloxazole

In a round-bottomed flask under N₂, a solution of2-methyloxazol-4-yl)methanol (5.40 g, 26.8 mmol) in CH2C12 (56.0 mL) wastreated at rt with tert-butylchlorodimethylsilane (8.52 g, 53.7 mmol)followed by imidazole (3.69 g, 53.67 mmol) and the resulting suspensionwas stirred for 1 h at rt. Water was then added, and the mixtureextracted with CH₂Cl₂. The organic layers were dried over Na₂SO₄,filtered, concentrated, and purified via column chromatography(heptane/ethyl acetate) to give the desired product. LC-MS calculatedfor C₁₁H₂₂NO₂Si: 228.1 (M+H)⁺; found: 228.3 (M+H)⁺.

Step B.4-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-5-(4,4.5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)amzole

Under N₂ atmosphere, a flask was charged with [Ir(OMe)(1,5-cod)]₂ (1 3mg, 0.019 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.085 mL, 0.58mmol), and pentane (2.0 mL).

The resulting mixture was stirred at room temperature for 10 to 15 min.4,4′-Di-tert-butyl-2,2′-dipyridyl (dtbpy) (10.5 mg, 0.039 mmol) wasadded, and the reaction mixture was stirred for additional 20 min.4-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyloxazole (83 mg, 0.39mmol) in diethyl ether (2.0 mL) was then added, and the resultingmixture was stirred at room temperature until completion. Solvent wasremoved under reduced pressure, and the crude material was washed withpentane to furnish the desired product. LC-MS calculated forC₁₇H₃₃BNO₄Si: 354.2 (M+H)⁺; found: 354.2 (M+H)⁺.

Step C3-(4-conino-7-(4-(hvdrox:Inethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

Cesium carbonate (77 mg, 0.236 mmol) was added to the mixture of3-(4-amino-7-bromo-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile(50 mg, 0.118 mmol) and4-4(tert-butyldimethylsilyl)oxy)methyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole(83 mg, 0.236 mmol) in 1,4-dioxane (2.0 mL) and Water (0.20 mL). Thereaction was sparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl]palladium(II)(9.20mg, 0.012 mmol) was added. The reaction was stirred at 120° C. for 1.5h.

To the reaction mixture was added TFA (1.0 mL, 12.98 mmol). The reactionmixture was stirred at 100° C. for 1 h. The reaction mixture was dilutedwith methanol. Direct purification on prep. HPLC afforded the desiredproduct. LC-MS calculated for C₂₃H₁₈FN₈O₂: 457.2 (M+H)⁺; found: 457.3(M+H)⁺.

Example 433-(4-amino-2-(pyridin-2-ylmethyl)-7-(quinoxalin-6-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

The title compound was synthesized according to the procedure describedin Example 38, except by using quinoxalin-6-ylboronic acid instead ofusing (1-ethyl-1H-pyrazol-5-yl)boronic acid. LC-MS calculated forC₂₆H₁₇FN₉: 474.2 (M+H)⁺; found: 474.3 (M+H)⁺.

Example 443-(4-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Step A6-chloro-N-(2,4-dimethoxybenzyl)-2-((1-methyl-1H-pyrazol-3-yOmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine

To the mixture of6-chloro-N-(2,4-dimethoxybenzyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(1000 mg, 3.13 mmol), (1-methyl-1H-pyrazol-3-yl)methanol (421 mg, 3.75mmol) and triphenylphosphine (1641 mg, 6.25 mmol) in DCM (10 mL) wasadded diisopropyl azodicarboxylate (0.739 mL, 3.75 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 1 h. Direct purification onsilica gel column afforded the desired product(345 mg, 27%). LC-MScalculated for C₁₉H₂₁ClN₇O₂: 414.1 (M+H)⁺; found: 414.2 (M+H)⁺.

Step B.3-(4-((2,4-dimethoxybenzyl)amino)-2-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (543 mg, 1.667 mmol) was added to the mixture of6-chloro-N-(2,4-dimethoxybenzyl)-2-((l-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo [4,5-c]pyridin-4-amine (345 mg, 0.834mmol), (3-cyanophenyl)boronic acid (245 mg, 1.667 mmol) in 1,4-dioxane(10 ml) and water (1.00 ml). The reaction was sparged with N₂ for 2 minandchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(65.6 mg, 0.083 mmol) was added. The reaction was stirred at 120° C. for1.5 h. The reaction was quenched with 20 mL of ethyl acetate and 20 mLof water. The organic phase was separated and the aqueous solution wasextracted with ethyl acetate twice. The combined extracts were driedover Na₂SO₄, filtered and evaporated under reduced pressure. The residuewas purified on silica gel column to afford the desired product (305 mg,76%). LC-MS calculated for C₂₆H₂₅N₈O₂: 481.2 (M+H)⁺; found: 481.3(M+H)⁺.

Step C.3-(4-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The solution of3-(4-((2,4-dimethoxybenzyl)amino)-2-((l-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(305.3 mg, 0.635 mmol) in TFA (5 mL) was stirred at 100° C. for 1 h. TFAwas evaporated under reduced pressure and then 20 mL of saturated NaHCO₃aqueous solution and 20 mL of ethyl acetate were added. The organicphase was separated and the aqueous solution was extracted with ethylacetate twice. The combined extracts were dried over Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified onsilica gel column to afford the desired product (159 mg, 76%). LC-MScalculated for C₁₇H₁₅N₈: 331.1 (M+H)⁺; found: 331.3 (M+H)⁺.

Step D.3-(4-amino-7-bromo-2-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of3-(4-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yObenzonitrile(159 mg, 0.481 mmol) and 1-bromopyrrolidine-2,5-dione (90 mg, 0.505mmol) in THF (10 mL) was stirred at 0° C. for 1 h. Direct purificationon silica gel column afforded the desired product (149 mg, 76%). LC-MScalculated for C₁₇H₁₄BrN₈: 409.1 (M+H)⁺ and 411.1 (M+H)⁺; found: 409.3(M+H)⁺and 411.3 (M+H)⁺.

Step E.3-(4-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of3-(4-amino-7-bromo-2-((l-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(220 mg, 0.538 mmol), 4-(tributylstannyl)pyrimidine (50 mg, 0.135 mmol),and copper(I) chloride (63.9 mg, 0.645 mmol), lithium chloride (27.3 mg,0.645 mmol) and tetrakis(triphenylphosphine)palladium(0) (62.1 mg, 0.054mmol) in THF (1 ml) was first purged with N₂, and then heated andstirred at 90° C. for 2 h. The reaction was diluted with methanol andpurified with prep-LCMS (pH 2) to give the desired compound. LC-MScalculated for C₂₁H₁₇N₁₀: 409.2 (M+H)⁺; found: 409.3 (M+H)⁺.

Example 453-(4-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4-methyloxazol-5-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (159 mg, 0.489 mmol) was added to the mixture of3-(4-amino-7-bromo-2-((l-methyl-1H-pyrazol-3-yl)methyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile (100 mg, 0.244 mmol) and4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (102 mg,0.489 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL). The reaction wassparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(17 mg, 0.024 mmol) was added. The reaction was stirred at 120° C. for1.5 h. The reaction mixture was diluted with methanol. Directpurification on prep. HPLC afforded the desired product. LC-MScalculated for C₂₁H₁₈N₉O: 412.2 (M+H)⁺; found: 412.3 (M+H)⁺.

Example 463-(4-amino-7-(4-methyloxazol-5-yl)-2-(1-(pyridin-2-ypethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Step A.6-chloro-N-(2,4-dimethoxybenzyl)-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine

The mixture of6-chloro-N-(2,4-dimethoxybenzyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(1000 mg, 3.13 mmol), 1-(pyridin-2-yl)ethan-1-ol (462 mg, 3.75 mmol),triphenylphosphine (1641 mg, 6.25 mmol) and diisopropyl azodicarboxylate(0.739 mL, 3.75 mmol) was stirred at 0° C. for 1 h. Direct purificationon silica gel column afforded the desired product (359 mg, 27%). LC-MScalculated for C₂₁H₂₂ClN₆O₂: 425.1 (M+H)⁺; found: 425.3 (M+H)⁺.

Step B.3-(4-((2,4-dimethoxybenzyl)amino)-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (551 mg, 1.690 mmol) was added to the mixture of6-chloro-N-(2,4-dimethoxybenzyl)-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-4-amine(359 mg, 0.845 mmol) and (3-cyanophenyl)boronic acid (248 mg, 1.690mmol) in 1,4-dioxane (10 mL) and Water (1.00 mL). The resulting reactionmixture was sparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(66.5 mg, 0.084 mmol) was added. The reaction was stirred at 120° C. for1.5 h. The reaction was quenched with 20 mL of ethyl acetate and 20 mLof water. The organic phase was separated and the aqueous solution wasextracted with ethyl acetate twice. The combined extracts were driedover Na₂SO₄, filtered and evaporated under reduced pressure. The residuewas purified on silica gel column to afford the desired product (347 mg,84%). LC-MS calculated for C₂₈H₂₆N₇O₂: 492.2 (M+H)⁺; found: 492.3(M+H)⁺.

Step C.3-(4-amino-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The solution of3-(4-((2,4-dimethoxybenzyl)amino)-2-(1-(pyridin-2-ypethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(347 mg, 0.707 mmol) in TFA (5.00 mL) was stirred at 100° C. for 1 h.TFA was evaporated under reduced pressure and then 20 mL of saturatedNaHCO₃ aqueous solution and 20 mL of ethyl acetate were added. Theorganic phase was separated and the aqueous solution was extracted withethyl acetate twice. The combined extracts were dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedon silica gel column to afford the desired product (200 mg, 83%). LC-MScalculated for C₁₉H₁₆N₇: 342.1 (M+H)⁺; found: 342.3 (M+H)⁺.

Step D.3-(4-amino-7-bromo-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The mixture of 3 -(4-amino-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile (200 mg, 0.586 mmol) and1-bromopyrrolidine-2,5-dione (115 mg, 0.644 mmol) in THF (10 ml) wasstirred at 0° C. for 1 h. Direct purification on silica gel columnafforded the desired product (197 mg, 80%). LC-MS calculated forC₁₉H₁₅BrN₇: 420.1 (M+H)⁺and 422.1(M+H)⁺; found: 420.3 (M+H)⁺and 422.3(M+H)⁺.

Step E.3-(4-amino-7-(4-methyloxazol-5-yl)-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

Cesium carbonate (132 mg, 0.404 mmol) was added to the mixture of3-(4-amino-7-bromo-2-(1-(pyridin-2-yl)ethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile(85 mg, 0.202 mmol) and4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (85 mg,0.404 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL). The resultingmixture was sparged with N₂ for 2 min andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl]palladium(II)(0.020 mmol) was added. The reaction was stirred at 120° C. for 1.5 h.The reaction mixture was diluted with methanol. Direct purification onprep. HPLC afforded the desired product. LC-MS calculated for C₂₃H₁₉N₈O:423.2 (M+H)⁺; found: 423.3 (M+H)⁺.

Example 473-(4-amino-2-(1-(pyridin-2-yl)ethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

A mixture of3-(4-amino-7-bromo-2-(1-(pyridin-2-ypethyl)-2H-[1,2,3]triazolo[4,5-cl]yridin-6-yl)benzonitrile(85 mg, 0.202 mmol), 4-(tributylstannyl)pyrimidine (50 mg, 0.135 mmol),and copper(I) chloride (24.03 mg, 0.243 mmol), lithium chloride (10.29mg, 0.243 mmol) and tetrakis(triphenylphosphine)palladium(0) (23.37 mg,0.020 mmol) in THF (1 ml) was first purged with N₂, and then heated andstirred at 90 C for 2 h. The reaction was diluted with methanol andpurified with prep-LCMS (pH=2) to give the desired product. LC-MScalculated for C₂₃H₁₈N₉: 420.2 (M+H)⁺; found: 420.3 (M+H)⁺.

Example 483-(4-amino-7-(4-methyloxazol-5-yl)-2-(2-(pyridin-2-ypethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 46, except by using 2-(pyridin-2-yl)ethan-1-olinstead of using 1-(pyridin-2-yl)ethan-1-ol in step A. LC-MS calculatedfor C₂₃H₁₉N₈O: 423.2 (M+H)⁺; found: 423.3 (M+H)⁺.

Example 493-(4-amino-7-(4-methyloxazol-5-yl)-2-(2-(pyridin-2-ypethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile

The above title compound was synthesized according to the proceduredescribed in Example 48, except by using (2-fluoro-3-cyanophenyl)boronicacid instead of using (3-cyanophenyl)boronic acid. LC-MS calculated forC₂₃H₁₈FN₈O: 441.2 (M+H)+; found: 441.3 (M+H)⁺.

Example A. Adenosine A2A Receptor Cyclic AMP GS Assay

Stably transfected HEK-293 cells expressing the human adenosine A2Areceptor (Perkin Elmer) are maintained in MEM culture medium with 10%FBS and 400 μg/mL Geneticin (Life Technologies). 18 to 24 hours prior toassay, geneticin is removed from culture. The cisbio cAMP-GS Dynamic kitutilizing the FRET (Fluorescence Resonance Energy Transfer) technologyis used to measure cAMP accumulation in the cells. Compounds of thepresent disclosure at an appropriate concentration are mixed with 10000cells/well in white 96 well half area plates (Perkin Elmer) for 30 minat RT gently shaking. Agonist, CGS21680 (R&D Technologies) at 4 nM isadded to each well for 60 min at room temperature gently shaking.Detection reagents, d2-labeled cAMP (acceptor) and anti-cAMP cryptate(donor) are added to each well for 60 min at room temperature gentlyshaking. Plates are read on Pherastar (BMG Labtech), fluorescence ratio665/620 is calculated and EC₅₀ determination is performed by fitting thecurve of percent of control versus the log of the compound concentrationusing GraphPad Prism.

Example B. Adenosine A2B Receptor Cyclic AMP GS Assay

Stably transfected HEK-293 cells expressing the human adenosine A2Breceptor (Perkin Elmer) were maintained in MEM culture medium with 10%FBS and 100 μg/mL Geneticin (Life Technologies). 18 to 24 hours prior toassay, geneticin was removed from culture. The cisbio cAMP-GS Dynamickit utilizing the FRET (Fluorescence Resonance Energy Transfer)technology was used to measure cAMP accumulation in the cells. Compoundsof the present disclosure at an appropriate concentration were mixedwith 10000 cells/well in white 96 well half area plates (Perkin Elmer)for 30 min at room temperature gently shaking. Agonist, NECA (R&DTechnologies) at 12 nM was added to each well for 60 min at roomtemperature gently shaking. Detection reagents, d2-labeled cAMP(acceptor) and anti-cAMP cryptate (donor) were added to each well for 60min at RT gently shaking. Plates were read on Pherastar (BMG Labtech),fluorescence ratio 665/620 was calculated and ECso determination wasperformed by fitting the curve of percent of control versus the log ofthe compound concentration using GraphPad Prism. The ECso data for theExamples obtained via this method are shown in Table 1.

TABLE 1 The A_(2A)_Ki data and A_(2B)_cAMP_EC₅₀ data are provided below.The symbol “†” indicates A_(2A)_Ki or A_(2B)_cAMP_EC₅₀ ≤ 10 nM, “††”indicates A_(2A)_Ki or A_(2B)_cAMP_EC₅₀ > 10 nM but ≤ 100 nM. “†††”indicates A_(2A)_Ki or A_(2B)_cAMP_EC₅₀ > 100 nM but ≤ l μM; and “††††”indicates A_(2A)_Ki or A_(2B)_cAMP_EC₅₀ is greater than 1 μM. A_(2A)_KiA_(2B)_cAMP_EC₅₀ Ex. No. (nM) (nM)  1 † ††  2 † †  3 † ††  4 † ††  5 NANA  6 † †  7 † †  8 † †  9 † † 10 † † 11 † †† 12 † †† 13 † †† 14 † † 15NA NA 16 † † 17 † † 18 † † 19 † † 20 † † 21 † † 22 † † 23 † ††† 24 † †25 † † 26 † † 27 † †† 28 † † 29 † † 30 † † 31 † † 32 † †† 33 † † 34 † †35 † † 36 † † 37 † †† 38 † † 39 † † 40 † † 41 † † 42 † †† 43 † ††† 44 †† 45 † † 46 † † 47 † ††† 48 † †† 49 † ††

Example C. A2A Tag-Lite® HTRF Assay

Assays were conducted in black low volume 384-well polystyrene plates(Greiner 784076-25) in a final volume of 10 μL. Test compounds werefirst serially diluted in DMSO and 100 nl added to the plate wellsbefore the addition of other reaction components. The finalconcentration of DMSO was 1%. Tag-lite® Adenosine A2A labeled cells(CisBio C1TT1A2A) were diluted 1:5 into Tag-lite buffer (CisBio LABMED)and spun 1200 g for 5 mins. The pellet was resuspended at a volume 10.4×the initial cell suspension volume in Tag-lite buffer, and Adenosine A2AReceptor Red antagonist fluorescent ligand (CisBio L0058RED) added at12.5 nM final concentration. 10 ul of the cell and ligand mix was addedto the assay wells and incubated at room temperature for 45 minutesbefore reading on a PHERAstar FS plate reader (BMG Labtech) with HTRF337/620/665 optical module. Percent binding of the fluorescent ligandwas calculated; where 100 nM of A2A antagonist control ZM 241385 (Tocris1036) displaces the ligand 100% and 1% DMSO has 0% displacement. The %binding data versus the log of the inhibitor concentration was fitted toa one-site competitive binding model (GraphPad Prism version 7.02) wherethe ligand constant =12.5 nM and the ligand Kd =1.85 nM. The K_(i) datafor the Examples obtained via this method are shown in Table 1 (SeeExample B).

Example D. A2B Filter Binding Assay

Assays are conducted in deep well polypropylene plates (Greiner 786201)in a final volume of 550 μL. Test compounds are first serially dilutedin DMSO and 5.5ul is then added to the plate wells before the additionof other reaction components. The final concentration of DMSO is 3%.HEK293 cell membranes overexpressing the human adenosine receptor A2B(Perkin Elmer ES-113-M400UA) are diluted to 40 ug/mL in 50 mM HEPES pH7.0, 5 mM MgC12, 1 mM EDTA (Assay buffer). [3H]8-cyclopentyl-1,3-dipropylxanthine (Perkin Elmer NET974001MC) is dilutedin assay buffer +22% DMSO to 24.2 nM, and then further diluted to 1 nMby addition to the diluted membranes. 545 ul of the membrane and ligandmix is added to the assay wells and incubated on a shaker at roomtemperature for 1 hour. The membrane mix is then filtered over aUniFilter GF/C filter plate (Perkin Elmer 6005174) pre-soaked in 50 mMHEPES pH 6.5, 5 mM MgCl₂, 1mM EDTA 0.5% BSA and then washed with 5 mLice cold 50 mM HEPES pH 6.5, 5 mM MgCl₂, 1 mM EDTA 0.2% BSA. 50 ulMicroScint™ cocktail (Perkin Elmer 6013621) is added and plates are readon a Topcount NXT FS (Perkin Elmer). Percent binding of the [3H] ligandis calculated, where 1000 nM of LUF 5834 (Tocris 4603) control displacesthe ligand 100% and 3% DMSO has 0% displacement. The % binding dataversus the log of the inhibitor concentration is fitted to a one-sitecompetitive binding model (GraphPad Prism version 7.02) where the ligandconstant=2 nM and the ligand Kd=13 nM.

Example E. A1 and A3 SPA Binding Assays

Both assays are conducted in white 384-well polystyrene plates (Greiner781075) in a final volume of 50 μL. Inhibitors are first seriallydiluted in DMSO and 100 nL is added to the plate wells before theaddition of other reaction components. The final concentration of DMSOis 2%.

Wheatgerm agglutinin-coated yttrium silicate SPA beads (Perkin ElmerRPNQ0023) and CHO-K1 cell membranes overexpressing each human adeonsinereceptor are incubated in 50 mM HEPES pH 7.0, 5 mM MgCl₂, 1 mM EDTA(Assay buffer) on a rotary stirrer for 2 hours at 4° C. The beads arepelleted by centrifugation at 6000 g for one minute, and then thesupernatant with unbound membrane is discarded. The beads arere-suspended to the original volume in assay buffer. Each radioligand isdiluted in assay buffer +22% DMSO at 12.2X the final concentration, andthen added to the SPA bead suspension. 50 μl of the SPA bead reactionmix is added to the assay wells and the plates shaken at 600 rpm for 1hour at room temperature. The beads are then allowed to settle for 1hour before reading on a Topcount NXT FS (Perkin Elmer). Percent bindingof the radiolabeled ligand is calculated, where a control at >100X Kidisplaces the ligand 100% and 2% DMSO has 0% displacement. The % bindingdata versus the log of the inhibitor concentration is fitted to aone-site competitive binding model (GraphPad Prism version 7.02).

Assay conditions are provided in Table A below.

TABLE A Assay Component A1 A3 SPA beads in  3 mg/mL 1.25 mg/mL Hepesbuffer Membrane 60 μg/mL   20 μg/mL Perkin Elmer ES-010 Perkin ElemerES-012 Radioligand l nM [3H] DP-CPX 0.1 nM [125I] MECA (Perkin ElmerNET974) (Perkin Elmer NEX312) K_(D) = 1 nM K_(D) = 0.8 nM Control 1 μMDPCPX 0.1 μM IB-MECA (Tocris 0439) (Tocris 1066)

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. 1-49. (canceled)
 50. A method of treating a disease or disorderselected from bladder cancer, lung cancer, breast cancer, ovariancancer, colorectal cancer, prostate cancer, and head and neck cancer ina patient, comprising administering to said patient a therapeuticallyeffective amount of3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)benzonitrile,or a pharmaceutically acceptable salt thereof.
 51. The method of claim50, wherein the disease or disorder is head and neck cancer.
 52. Themethod of claim 51, wherein the head and neck cancer is head and necksquamous cell carcinoma.
 53. The method of claim 50, wherein the diseaseor disorder is lung cancer.
 54. The method of claim 53, wherein the lungcancer is non-small cell lung cancer (NSCLC).
 55. The method of claim50, wherein the disease or disorder is ovarian cancer.
 56. The method ofclaim 50, wherein the disease or disorder is prostate cancer.
 57. Themethod of claim 56, wherein the prostate cancer is metastaticcastration-resistant prostate cancer.
 58. The method of claim 50,wherein the disease or disorder is breast cancer.
 59. The method ofclaim 50, wherein the disease or disorder is bladder cancer.
 60. Themethod of claim 50, wherein the disease or disorder is colorectalcancer.
 61. The method of claim 50, wherein the disease or disorder ispancreatic cancer.